N-substituted benzamides and methods of use thereof

ABSTRACT

The invention provides novel compounds having the general formula: 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof, wherein the variables R A , subscript n, ring A, X 2 , L, subscript m, X 1 , B, R 1 , R 2 , R 3 , R 4 , R 5  and R N  have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

PRIORITY OF INVENTION

This application claims priority under 35 U.S.C. 119(a) and 35 U.S.C.365(a) to international patent application number PCT/1132012/001324,filed 22 May 2012; this application also claims priority under 35 U.S.C.119(e) to U.S. Provisional Patent Application No. 61/650,934, filed 23May 2012 and under 35 U.S.C. 119(e) to U.S. Provisional PatentApplication No. 61/785,601, filed 14 Mar. 2013. The entire content ofthe applications referenced above are hereby incorporated by referenceherein.

FIELD OF THE INVENTION

The present invention relates to organic compounds useful for therapyand/or prophylaxis in a mammal, and in particular to inhibitors ofsodium channel (e.g., NAV1.7) that are useful for treating sodiumchannel-mediated diseases or conditions, such as pain, as well as otherdiseases and conditions associated with the mediation of sodiumchannels.

Voltage-gated sodium channels, transmembrane proteins that initiateaction potentials in nerve, muscle and other electrically excitablecells, are a necessary component of normal sensation, emotions, thoughtsand movements (Catterall, W. A., Nature (2001), Vol. 409, pp. 988-990).These channels consist of a highly processed alpha subunit that isassociated with auxiliary beta subunits. The pore-forming alpha subunitis sufficient for channel function, but the kinetics and voltagedependence of channel gating are in part modified by the beta subunits(Goldin et al., Neuron (2000), Vol. 28, pp. 365-368).Electrophysiological recording, biochemical purification, and molecularcloning have identified ten different sodium channel alpha subunits andfour beta subunits (Yu, F. H., et al., Sci. STKE (2004), 253; and Yu, F.H., et al., Neurosci. (2003), 20:7577-85).

The hallmarks of sodium channels include rapid activation andinactivation when the voltage across the plasma membrane of an excitablecell is depolarized (voltage-dependent gating), and efficient andselective conduction of sodium ions through conducting pores intrinsicto the structure of the protein (Sato, C., et al., Nature (2001),409:1047-1051). At negative or hyperpolarized membrane potentials,sodium channels are closed. Following membrane depolarization, sodiumchannels open rapidly and then inactivate. Channels only conductcurrents in the open state and, once inactivated, have to return to theresting state, favoured by membrane hyperpolarization, before they canreopen. Different sodium channel subtypes vary in the voltage range overwhich they activate and inactivate as well as their activation andinactivation kinetics.

The sodium channel family of proteins has been extensively studied andshown to be involved in a number of vital body functions. Research inthis area has identified variants of the alpha subunits that result inmajor changes in channel function and activities, which can ultimatelylead to major pathophysiological conditions. The members of this familyof proteins are denoted NaV1.x, where x=1 to 9. NaV1.1 and NaV1.2 arehighly expressed in the brain (Raymond, C. K., et al., J. Biol. Chem.(2004), 279(44):46234-41) and are vital to normal brain function. Someloss of function mutations in NaV1.1 in humans result in epilepsy,apparently because many of these channels are expressed in inhibitoryneurons (Yu, F. H., et al., Nat Neurosci (2006), 9 (9), 1142-9). Thus,block of NaV1.1 in the CNS may be counter-productive because it canproduce hyperexcitability. However, NaV1.1 is also expressed in theperipheral nervous system and block may afford analgesic activity.

NaV1.3 is expressed primarily in the fetal central nervous system. It isexpressed at very low levels or not at all in the peripheral nervoussystem, but expression is upregulated in the dorsal horn sensory neuronsof rats after nervous system injury (Hains, B. D., et al., J. Neurosci.(2003), 23(26):8881-92). Thus, it is an inducible target for treatmentof pain following nerve injury.

NaV1.4 is expressed primarily in skeletal muscle (Raymond, C. K., etal., op. cit.). Mutations in this gene have been shown to have profoundeffects on muscle function including paralysis, (Tamaoka A., Intern.Med. (2003), (9):769-70).

NaV1.5, is expressed mainly in cardiac myocytes (Raymond, C. K., et al.,op. cit.), including atria, ventricles, the sin θ-atrial node,atrio-ventricular node and cardiac Purkinje fibers. The rapid upstrokeof the cardiac action potential and the rapid impulse conduction throughcardiac tissue is due to the opening of NaV1.5. Abnormalities in thefunction of NaV1.5 can result in the genesis of a variety of cardiacarrhythmias. Mutations in human NaV1.5 result in multiple arrhythmicsyndromes, including, for example, long QT3 (LQT3), Brugada syndrome(BS), an inherited cardiac conduction defect, sudden unexpectednocturnal death syndrome (SUNDS) and sudden infant death syndrome (SIDS)(Liu, H., et al., Am. J. Pharmacogenomics (2003), 3(3):173-9). Sodiumchannel blocker therapy has been used extensively in treating cardiacarrhythmias.

NaV1.6 is a widely distributed voltage-gated sodium channel foundthroughout the central and peripheral nervous systems. It is expressedat high density in the nodes of Ranvier of myelinated neurons (Caldwell,J. H., et al., Proc. Natl. Acad. Sci. USA (2000), 97(10): 5616-20).

NaV1.7 is a tetrodotoxin-sensitive voltage-gated sodium channel encodedby the gene SCN9A. Human NaV1.7 was first cloned from neuroendocrinecells (Klugbauer, N., et al., 1995 EMBO J., 14 (6): 1084-90.) and ratNaV1.7 was cloned from a pheochromocytoma PC12 cell line (Toledo-Aral,J. J., et al., Proc. Natl. Acad. Sci. USA (1997), 94:1527-1532) and fromrat dorsal root ganglia (Sangameswaran, L., et al., (1997), J. Biol.Chem., 272 (23): 14805-9). NaV1.7 is expressed primarily in theperipheral nervous system, especially nocieptors and olfactory neuronsand sympathetic neurons. The inhibition, or blocking, of NaV1.7 has beenshown to result in analgesic activity. Knockout of NaV1.7 expression ina subset of sensory neurons that are predominantly nociceptive resultsin resistance to inflammatory pain (Nassar, et al., op. cit.). Likewise,loss of function mutations in humans results in congenital indifferenceto pain (CIP), in which the individuals are resistant to bothinflammatory and neuropathic pain (Cox, J. J., et al., Nature (2006);444:894-898; Goldberg, Y. P., et al., Clin. Genet. (2007); 71:311-319).Conversely, gain of function mutations in NaV1.7 have been establishedin two human heritable pain conditions, primary erythromelalgia andfamilial rectal pain, (Yang, Y., et al., J. Med. Genet. (2004),41(3):171-4). In addition, a single nucleotide polymorphism (R1150W)that has very subtle effects on the time- and voltage-dependence ofchannel gating has large effects on pain perception (Estacion, M., etal., 2009. Ann Neurol 66: 862-6; Reimann, F., et al., Proc Natl Acad SciUSA (2010), 107: 5148-53). About 10% of the patients with a variety ofpain conditions have the allele conferring greater sensitivity to painand thus might be more likely to respond to block of NaV1.7. BecauseNaV1.7 is expressed in both sensory and sympathetic neurons, one mightexpect that enhanced pain perception would be accompanied bycardiovascular abnormalities such as hypertension, but no correlationhas been reported. Thus, both the CIP mutations and SNP analysis suggestthat human pain responses are more sensitive to changes in NaV1.7currents than are perturbations of autonomic function.

NaV1.8 is expressed primarily in sensory ganglia of the peripheralnervous system, such as the dorsal root ganglia (Raymond, C. K., et al.,op. cit.). There are no identified human mutations for NaV1.8 thatproduce altered pain responses. NaV1.8 differs from most neuronal NaV'sin that it is insensitive to block by tetrodotoxin. Thus, one canisolate the current carried by this channel with tetrodotoxin. Thesestudies have shown that a substantial portion of total sodium current isNaV1.8 in some dorsal root ganglion neurons (Blair, N. T., et al., JNeurosci (2002), 22: 10277-90). Knock-down of NaV1.8 in rats has beenachieved by using antisense DNA or small interfering RNAs and virtuallycomplete reversal of neuropathic pain was achieved in the spinal nerveligation and chronic constriction injury models (Dong, X. W., et al.,Neuroscience (2007), 146: 812-21; Lai J., et al. Pain (2002), 95:143-52). Thus, NaV1.8 is considered a promising target for analgesicagents based upon the limited tissue distribution of this NaV isoformand the analgesic activity produced by knock-down of channel expression.

NaV1.9 is also a tetrodotoxin insensitive, sodium channel expressedprimarily in dorsal root ganglia neurons (Dib-Hajj, S. D., et al. (seeDib-Hajj, S. D., et al., Proc. Natl. Acad. Sci. USA (1998),95(15):8963-8). It is also expressed in enteric neurons, especially themyenteric plexus (Rugiero, F., et al., J Neurosci (2003), 23: 2715-25).The limited tissue distribution of this NaV isoform suggests that it maybe a useful target for analgesic agents (Lai, J., et al., op. cit.;Wood, J. N., et al., op. cit.; Chung, J. M., et al., op. cit.).Knock-out of NaV1.9 results in resistance to some forms of inflammatorypain (Amaya, F., et al., J Neurosci (2006), 26: 12852-60; Priest, B. T.,et al., Proc Natl Acad Sci USA (2005), 102: 9382-7).

This closely related family of proteins has long been recognized astargets for therapeutic intervention. Sodium channels are targeted by adiverse array of pharmacological agents. These include neurotoxins,antiarrhythmics, anticonvulsants and local anesthetics (England, S., etal., Future Med Chem (2010), 2: 775-90; Termin, A., et al., AnnualReports in Medicinal Chemistry (2008), 43: 43-60). All of the currentpharmacological agents that act on sodium channels have receptor siteson the alpha subunits. At least six distinct receptor sites forneurotoxins and one receptor site for local anesthetics and relateddrugs have been identified (Cestèle, S., et al., Biochimie (2000), Vol.82, pp. 883-892).

The small molecule sodium channel blockers or the local anesthetics andrelated antiepileptic and antiarrhythmic drugs interact with overlappingreceptor sites located in the inner cavity of the pore of the sodiumchannel (Catterall, W. A., Neuron (2000), 26:13-25). Amino acid residuesin the S6 segments from at least three of the four domains contribute tothis complex drug receptor site, with the IVS6 segment playing thedominant role. These regions are highly conserved and as such mostsodium channel blockers known to date interact with similar potency withall channel subtypes. Nevertheless, it has been possible to producesodium channel blockers with therapeutic selectivity and a sufficienttherapeutic window for the treatment of epilepsy (e.g., lamotrignine,phenyloin and carbamazepine) and certain cardiac arrhythmias (e.g.,lignocaine, tocamide and mexiletine). However, the potency andtherapeutic index of these blockers is not optimal and have limited theusefulness of these compounds in a variety of therapeutic areas where asodium channel blocker would be ideally suited.

Sodium channel blockers have been shown to be useful in the treatment ofpain, including acute, chronic, inflammatory and/or neuropathic pain(see, e.g., Wood, J. N., et al., J. Neurobiol. (2004), 61(1), 55-71.Preclinical evidence demonstrates that sodium channel blockers cansuppress neuronal firing in peripheral and central sensory neurons, andit is via this mechanism that they are considered to be useful forrelieving pain. In some instances, abnormal or ectopic firing canoriginal from injured or otherwise sensitized neurons. For example, ithas been shown that sodium channels can accumulate in peripheral nervesat sites of axonal injury and may function as generators of ectopicfiring (Devor et al., J. Neurosci. (1993), 132: 1976). Changes in sodiumchannel expression and excitability have also been shown in animalmodels of inflammatory pain where treatment with proinflammatorymaterials (CFA, Carrageenan) promoted pain-related behaviors andcorrelated with increased expression of sodium channel subunits (Gouldet al., Brain Res., (1999), 824(2): 296-99; Black et al., Pain (2004),108(3): 237-47). Alterations in either the level of exprssion ordistribution of sodium channels, therefore, may have a major influenceon neuronal excitability and pain-related behaviors.

Controlled infusions of lidocaine, a known sodium channel blocker,indicate that the drug is efficacious against neuropathic pain, but hasa narrow therapeutic index. Likewise, the orally available localanesthetic, mexiletine, has dose-limiting side effects (Wallace, M. S.,et al., Reg. Anesth. Pain Med. (2000), 25: 459-67). A major focus ofdrug discovery targeting voltage-gated sodium channels has been onstrategies for improving the therapeutic index. One of the leadingstrategies is to identify selective sodium channel blockers designed topreferentially block NaV1.7, NaV1.8, NaV1.9 and/or NaV1.3. These are thesodium channel isoforms preferentially expressed in sensory neurons andunlikely to be involved in generating any dose-limiting side effects.For example, there is concern that blocking of NaV1.5 would bearrhythmogenic, so that selectivity of a sodium channel blocker againstNaV1.5 is viewed as highly desirable. Furthermore, nearly 700 mutationsof the SCN1A gene that codes for NaV1.1 have been identified in patientswith Severe Myoclonic Epilepsy of Infancy (SMEI), making this the mostcommonly mutated gene in human epilepsy. Half of these mutations resultin protein truncation (Meisler, M. H., et al., The Journal of Physiology(2010), 588: 1841-8). Thus, selectivity of a sodium channel blockeragainst NaV1.1 is also desirable.

In addition to the strategies of identifying selective sodium channelblockers, there is the continuing strategy of identifying therapeuticagents for the treatment of neuropathic pain. There has been some degreeof success in treating neuropathic pain symptoms by using medicationsoriginally approved as anticonvulsants, such as gabapentin, and morerecently pregabalin. However, pharmacotherapy for neuropathic pain hasgenerally had limited success for a variety of reasons: sedation,especially by drugs first developed as anticonvulsants oranti-depressants, addiction or tachyphylaxis, especially by opiates, orlack of efficacy, especially by NSAIDs and anti-inflammatory agents.Consequently, there is still a considerable need to explore noveltreatment modalities for neuropathic pain, which includes, but is notlimited to, post-herpetic neuralgia, trigeminal neuralgia, diabeticneuropathy, chronic lower back pain, phantom limb pain, and painresulting from cancer and chemotherapy, chronic pelvic pain, complexregional pain syndrome and related neuralgias.

There are a limited number of effective sodium channel blockers for thetreatment of pain with a minimum of adverse side effects which arecurrently in the clinic. There is also an unmet medical need to treatneuropathic pain and other sodium channel associated pathological stateseffectively and without adverse side effects due to the blocking ofsodium channels not involved in nociception. The present inventionprovides methods to meet these critical needs.

SUMMARY OF THE INVENTION

In one aspect the present invention provides for novel compounds. In afirst embodiment of such compounds (Embodiment 1; abbreviated as “E1”)the invention provides for compound selected from a compound of FormulaI:

and pharmaceutically acceptable salts thereof, wherein in Formula I:

R¹ is C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₁₂ cycloalkyl,C-linked C₂₋₁₁ heterocycloalkyl, heteroaryl, or NR^(1A)R^(1B), whereinR^(1A) and R^(1B) are each independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, C₁₋₈ alkoxy, (6-10 memberedaryl)-(X^(R1))₀₋₁—, (5-10 membered heteroaryl)-(X^(R1))₀₋₁—, and whereinR^(1A) and R^(1B) are optionally combined to form a 3 to 9 memberedheterocyclic ring optionally comprising 1 additional heteroatom selectedfrom N, O and S and optionally fused thereto is a benzene or pyridinering; X^(R1) is selected from the group consisting of C₁₋₄ alkylene,C₁₋₄ heteroalkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene; and wherein thealiphatic and aromatic portions of R¹ are optionally substituted withfrom 1 to 5 R^(R1) substituents selected from the group consisting ofC₁₋₈ alkyl, C₁₋₈ haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂, ═O,—(X^(1R))₀₋₁NR^(R1a)R^(R1b), —(X^(1R))₀₋₁OR^(R1a), —(X^(1R))₀₋₁SR^(R1a),—(X^(1R))₀₋₁N(R^(R1a))C(═O)OR^(R1c),—(X^(1R))₀₋₁OC(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))C(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁C(═O)N(R^(R1a))(R^(R1b)), (X^(1R))₀₋₁N(R^(R1a))C(═O)R^(R1b),—(X^(1R))₀₋₁C(═O)OR^(R1a), —(X^(1R))₀₋₁OC(═O)R^(R1a),—(X^(1R))₀₋₁—P(═O)(OR^(R1a))(OR^(R1b)), —(X^(1R))₀₋₁S(O)₁₋₂R^(R1c),—(X^(1R))₀₋₁S(O)₁₋₂N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))S(O)₁₋₂N(R^(R1a))(R^(R1b)) and—(X^(1R))₀₋₁N(R^(R1a))S(O)₁₋₂(R^(R1c)), wherein X^(1R) is selected fromthe group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein R^(R1a) and R^(R1b) areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, heteroaryl, andC₂₋₇ heterocycloalkyl; R^(R1c) is selected from the group consisting ofC₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, heteroaryl,and C₂₋₇ heterocycloalkyl;

R^(N) is hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

B is C or N;

R², R³ and R⁴ are each independently selected from the group consistingof H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy, andR³ is absent when B is nitrogen;

R⁵ is selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₈ cycloalkyl, C₂₋₇heterocycloalkyl, phenyl and 5-6 membered heteroaryl comprising 1 to 3heteroatoms selected from N, O and S, wherein said 5-6 memberedheteroaryl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl or C₂₋₇ heterocycloalkyl isfurther optionally substituted with from 1 to 3 R^(5a) substituentsselected from F, Cl, Br, I, —OH, ═O, C₃₋₆ cycloalkyl, —CN, C₁₋₄ alkyl,—C₁₋₄ alkyl-O—C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ alkoxy;

L is a linker selected from the group consisting of C₁₋₄ alkylene, C₂₋₄alkenylene, C₂₋₄ alkynylene, and C₁₋₄ heteroalkylene, wherein L isoptionally substituted with from 1 to 3 R^(L) substituents selected fromthe group consisting of ═O, —OH, —OCH2.phenyl, C₁₋₄ alkyl, C₁₋₄haloalkyl and C₁₋₄ acyl;

the subscript m represents the integer 0 or 1;

X¹ and X² are each independently selected from the group consisting ofabsent, —O—, —S(O)—, —S(O)₂— and —N(R^(X))— wherein R^(x) is H, C₁₋₈alkyl, C₁₋₈ acyl or —S(O)₂(C₁₋₈ alkyl), and wherein if the subscript mis 0 then at least one of X¹ or X² is absent;

the subscript n is an integer from 0 to 5;

A is selected from the group consisting of hydrogen, C₃₋₁₂ cycloalkyl,C₂₋₁₁ heterocycloalkyl, phenyl having a 3-8 membered carbocyclic orheterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and Sfused thereto or a 5 to 6 membered heteroaryl having a 3-8 memberedcarbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selectedfrom N, O and S fused thereto, and wherein if A is hydrogen then thesubscript n is 0; and

R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₃₋₈cycloalkyl, C₁₋₈ haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂, ═O,heteroaryl, —(X^(RA))₀₋₁NR^(A1)R^(A2), —(X^(RA))₀₋₁OR^(A1),—(X^(RA))₀₋₁SR^(A1), —(X^(RA))₀₋₁N(R^(A1))C(═O)OR^(A3),—(X^(RA))₀₋₁OC(═O)N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁N(R^(A1))C(═O)N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)), —(X^(RA))₀₋₁N(R^(A1))C(═O)R^(A2),—(X^(RA))₀₋₁C(═O)OR^(A1), —(X^(RA))₀₋₁OC(═O)R^(A1),—P(═O)(OR^(A1))(OR^(A2)), —(X^(RA))₀₋₁S(O)₁₋₂R^(A3),—(X^(RA))₀₋₁S(O)₁₋₂N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁)N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)) and—(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂(R^(A3)), wherein X^(RA) is selected fromthe group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein R^(A1) and R^(A2) areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl,tetrahydronapthalene, phenyl, benzyl, heteroaryl, and C₂₋₇heterocycloalkyl; R^(A3) is selected from the group consisting of C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, tetrahydronapthalene, phenyl,benzyl, heteroaryl, and C₂₋₇ heterocycloalkyl; wherein if A is amonocyclic C₃₋₁₂ carbocycloalkyl or monocyclic C₂₋₁₁ heterocycloalkyl,then any two R^(A) substituents attached to adjacent atoms on the A ringare optionally combined to form a benzene or a 5 to 6 memberedheteroaryl ring; and wherein the aliphatic and aromatic portions of aR^(A) substitutent is optionally substituted with from 1 to 5 R^(RA)substitutents selected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ (halo)alkyl-C(═O)—, C₁₋₄(halo)alkyl-S(O)₀₋₂—, C₁₋₄ (halo)alkyl-C(═O)N(H)—, C₁₋₄(halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)₂N—C(═O)—, C₁₋₄(halo)alkyl-OC(═O)N(H)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—,(halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylamino, C₁₋₄dialkylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxy, C₂₋₅ heterocycloalkoxy,tetrahydronaphthalene and phenyl wherein phenyl is optionallysubstituted with 1-3 fluoro, chloro, bromo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ ordialkylamino;

with the proviso that a compound of Formula I is not

-   4-(cyclohexylmethoxy)-N-(methylsulfonyl)benzamide;-   4-(cyclopentylmethoxy)-N-(methylsulfonyl)benzamide or-   4-(cyclobutylmethoxy)-2,5-difluoro-N-(methylsulfonyl)benzamide.

Further embodiments (E) of the first embodiment of compounds of theinvention, are described below.

E2 A compound of E1, wherein:

R¹ is C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₁₂ cycloalkyl,C-linked C₂₋₁₁ heterocycloalkyl, heteroaryl, or —NR^(1A)R^(1B), whereinR^(1A) and R^(1B) are each independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, C₁₋₈ alkoxy, (6-10 memberedaryl)-(X^(R1))₀₋₁—, (5-10 membered heteroaryl)-(X^(R1))₀₋₁—, and whereinR^(1A) and R^(1B) are optionally combined to form a 3 to 8 memberedheterocyclic ring optionally comprising 1 additional heteroatom selectedfrom N, O and S as ring vertex and optionally fused thereto is a benzeneor pyridine ring; X^(R1) is selected from the group consisting of C₁₋₄alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene; andwherein the aliphatic and aromatic portions of R¹ are optionallysubstituted with from 1 to 5 R^(R1) substituents selected from the groupconsisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂,═O, —(X^(1R))₀₋₁NR^(R1a)R^(R1b), —(X^(1R))₀₋₁OR^(R1a),—(X^(1R))₀₋₁SR^(R1a), —(X^(1R))₀₋₁N(R^(R1a))C(═O)OR^(R1c),—(X^(1R))₀₋₁OC(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))C(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁C(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))C(═O)R^(R1b), —(X^(1R))₀₋₁C(═O)OR^(R1a),—(X^(1R))₀₋₁OC(═O)R^(R1a), —(X^(1R))₀₋₁—P(═O)(OR^(R1a))(R^(R1b)),—(X^(1R))₀₋₁S(O)₁₋₂R^(R1c), —(X^(1R))₀₋₁S(O)₁₋₂N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))S(O)₁₋₂N(R^(R1a))(R^(R1b)) and—(X^(1R))₀₋₁N(R^(R1a)) S(O)₁₋₂(R^(R1c)), wherein X^(1R) is selected fromthe group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein R^(R1a) and R^(R1b) areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, heteroaryl, andC₂₋₇ heterocycloalkyl; R^(R1c) is selected from the group consisting ofC₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, heteroaryl,and C₂₋₇ heterocycloalkyl;

R^(N) is hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

B is C or N;

R², R³ and R⁴ are each independently selected from the group consistingof H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy, andR³ is absent when B is nitrogen;

R⁵ is selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₈ cycloalkyl, C₂₋₇heterocycloalkyl, phenyl and 5-6 membered heteroaryl comprising 1 to 3heteroatoms selected from N, O and S, wherein said 5-6 memberedheteroaryl is further optionally substituted with from 1 to 3 R⁵substituents selected from F, Cl, Br, I, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyland C₁₋₄ alkoxy;

L is a linker selected from the group consisting of C₁₋₄ alkylene, C₂₋₄alkenylene, C₂₋₄ alkynylene, and C₁₋₄ heteroalkylene, wherein L isoptionally substituted with from 1 to 3 R^(L) substituents selected fromthe group consisting of ═O, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ acyl;

the subscript m represents the integer 0 or 1;

X¹ and X² are each independently selected from the group consisting ofabsent, —O—, —S(O)—, —S(O)₂— and —N(R^(X))— wherein R^(x) is H, C₁₋₈alkyl, C₁₋₈ acyl or —S(O)₂(C₁₋₈ alkyl), and wherein if the subscript

m is 0 then one of X¹ or X² is absent;

the subscript n is an integer from 0 to 5;

A is selected from the group consisting of hydrogen, C₃₋₁₂ cycloalkyl,C₂₋₁₁ heterocycloalkyl, phenyl having a 3-8 membered carbocyclic orheterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and Sfused thereto or a 5 to 6 membered heteroaryl having a 3-8 memberedcarbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selectedfrom N, O and S fused thereto, and wherein if A is hydrogen then thesubscript n is 0; and

R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂, ═O, heteroaryl,—(X^(RA))₀₋₁NR^(A1)R^(A2), —(X^(RA))₀₋₁OR^(A1), —(X^(RA))₀₋₁SR^(A1),—(X^(RA))₀₋₁N(R^(A1))C(═O)OR^(A3), —(X^(RA))₀₋₁OC(═O)N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁N(R^(A1))C(═O)N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)), —(X^(RA))₀₋₁N(R^(A1))C(═O)R^(A2),—(X^(RA))₀₋₁C(═O)OR^(A1), —(X^(RA))₀₋₁OC(═O)R^(A1),—P(═O)(OR^(A1))(OR^(A2)), —(X^(RA))₀₋₁S(O)₁₋₂R^(A3),—(X^(RA))₀₋₁S(O)₁₋₂N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)) and—(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂(R^(A3)), wherein X^(RA) is selected fromthe group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein R^(A1) and R^(A2) areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, tetrahydronapthalene, phenyl,benzyl, heteroaryl, and C₂₋₇ heterocycloalkyl; R^(A3) is selected fromthe group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl,tetrahydronapthalene, phenyl, benzyl, heteroaryl, and C₂₋₇heterocycloalkyl; wherein if A is a monocyclic C₃₋₁₂ carbocycloalkyl ormonocyclic C₂₋₁₁ heterocycloalkyl, then any two R^(A) substituentsattached to adjacent atoms on the A ring are optionally combined to forma benzene or a 5 to 6 membered heteroaryl ring; and wherein thealiphatic and aromatic portions of a R^(A) substitutent is optionallysubstituted with from 1 to 5 R^(RA) substitutents selected from, F, Cl,Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ (halo)alkyl-C(═O)—, C₁₋₄ (halo)alkyl-S(O)₀₋₂—, C₁₋₄(halo)alkyl-C(═O)N(H)—, C₁₋₄ (halo)alkyl-N(H)—C(═O)—,((halo)alkyl)₂N—C(═O)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—, C₁₋₄(halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—,((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylamino, C₁₋₄ dialkylamino, C₃₋₆cycloalkyl, C₃₋₆ cycloalkoxy, C₂₋₅ heterocycloalkoxy andtetrahydronaphthalene;

with the proviso that a compound of Formula I is not

-   4-(cyclohexylmethoxy)-N-(methylsulfonyl)benzamide;-   4-(cyclopentylmethoxy)-N-(methylsulfonyl)benzamide or-   4-(cyclobutylmethoxy)-2,5-difluoro-N-(methylsulfonyl)benzamide.

E3 A compound of E1, wherein:

R¹ is C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₁₂ cycloalkyl,C-linked C₂₋₁₁ heterocycloalkyl or —NR^(1A)R^(1B), wherein R^(1A) andR^(1B) are each independently selected from the group consisting ofhydrogen, C₁₋₈ alkyl, C₁₋₈ alkoxy, (6-10 membered aryl)-(X^(R1))₀₋₁—,(5-10 membered heteroaryl)-(X^(R1))₀₋₁—, and wherein R^(1A) and R^(1B)are optionally combined to form a 3 to 8 membered heterocyclic ringoptionally comprising 1 additional heteroatoms selected from N, O and Sas ring vertex and optionally fused thereto is a benzene or pyridinering; X^(R1) is selected from the group consisting of C₁₋₄ alkylene,C₁₋₄ heteroalkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene; and wherein thealiphatic and aromatic portions of R¹ are optionally substituted withfrom 1 to 5 R^(R1) substituents selected from the group consisting ofC₁₋₈ alkyl, C₁₋₈ haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂,—(X^(1R))₀₋₁NR^(R1a)R^(R1b), —(X^(1R))₀₋₁OR^(R1a), —(X^(1R))₀₋₁SR^(R1a),—(X^(1R))₀₋₁N(R^(R1a))C(═O)OR^(R1c),—(X^(1R))₀₋₁C(═O)N(R^(R1a))(R^(R1b)),(X^(1R))₀₋₁N(R^(R1a))C(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁C(═O)N(R^(R1a))(R^(R1b)), (X^(1R))₀₋₁N(R^(R1a))C(═O)R^(R1b),—(X^(1R))₀₋₁C(═O)OR^(R1a), —(X^(1R))₀₋₁C(═O)R^(R1a),—(X^(1R))₀₋₁—P(═O)(OR^(R1a))(R^(R1b)), —(X^(1R))₀₋₁S(O)₁₋₂R^(R1c),—(X^(1R))₀₋₁S(O)₁₋₂N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))S(O)₁₋₂N(R^(R1a))(R^(R1b)) and—(X^(1R))₀₋₁N(R^(R1a))S(O)₁₋₂(R^(R1c)), wherein X^(1R) is selected fromthe group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein R^(R1a) and R^(R1b) areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, C₅₋₆ heteroaryland C₂₋₇ heterocycloalkyl; R^(R1c) is selected from the group consistingof C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, C₅₋₆heteroaryl and C₂₋₇ heterocycloalkyl;

R^(N) is hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

B is C or N;

R², R³ and R⁴ are each independently selected from the group consistingof H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy, andR³ is absent when B is nitrogen;

R⁵ is selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₈ cycloalkyl, C₂₋₇heterocycloalkyl, phenyl and 5-6 membered heteroaryl comprising 1 to 3heteroatoms selected from N, O and S, wherein said 5-6 memberedheteroaryl is further optionally substituted with from 1 to 3 R⁵substituents selected from F, Cl, Br, I, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyland C₁₋₄ alkoxy;

L is a linker selected from the group consisting of C₁₋₄ alkylene, C₂₋₄alkenylene, C₂₋₄ alkynylene, and C₁₋₄ heteroalkylene, wherein L isoptionally substituted with from 1 to 3 R^(L) substituents selected fromthe group consisting of ═O, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ acyl;

the subscript m represents the integer 0 or 1;

X¹ and X² are each independently selected from the group consisting ofabsent, —O—, —S(O)—, —S(O)₂— and —N(R^(X))— wherein R^(x) is C₁₋₈ alkyl,C₁₋₈ acyl or —S(O)₂(C₁₋₈ alkyl), and wherein if the subscript m is 0then one of X¹ or X² is absent;

the subscript n is an integer from 0 to 5;

A is selected from the group consisting of hydrogen, C₃₋₁₂ cycloalkyl,C₂₋₁₁ heterocycloalkyl, phenyl having a 3-8 membered carbocyclic orheterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and Sfused thereto or a 5 to 6 membered heteroaryl having a 3-8 memberedcarbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selectedfrom N, O and S fused thereto, and wherein if A is hydrogen then thesubscript n is 0; and

R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂, —(X^(RA))₀₋₁NR^(A1)R^(A2),—(X^(RA))₀₋₁OR^(A1), —(X^(RA))₀₋₁SR^(A1),—(X^(RA))₀₋₁N(R^(A1))C(═O)OR^(A3), —(X^(RA))₀₋₁OC(═O)N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁N(R^(A1))C(═O)N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)), —(X^(RA))₀₋₁N(R^(A1))C(═O)R^(A2),—(X^(RA))₀₋₁C(═O)OR^(A1), —(X^(RA))₀₋₁OC(═O)R^(A1),—P(═O)(OR^(A1))(OR^(A2)), —(X^(RA))₀₋₁S(O)₁₋₂R^(A3),—(X^(RA))₀₋₁S(O)₁₋₂N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)) and—(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂(R^(A3)), wherein X^(RA) is selected fromthe group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein R^(A1) and R^(A2) areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, tetrahydronapthalene, phenyl,benzyl, C₅₋₆ heteroaryl and C₂₋₇ heterocycloalkyl; R^(A3) is selectedfrom the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈cycloalkyl, tetrahydronapthalene, phenyl, benzyl, C₅₋₆ heteroaryl andC₂₋₇ heterocycloalkyl; wherein if A is a monocyclic C₃₋₁₂carbocycloalkyl or monocyclic C₂₋₁₁ heterocycloalkyl, then any two R^(A)substituents attached to adjacent atoms on the A ring are optionallycombined to form a benzene or a 5 to 6 membered heteroaryl ring; andwherein the aliphatic and aromatic portions of a R^(A) substitutent isoptionally substituted with from 1 to 5 R^(RA) substitutents selectedfrom, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ (halo)alkyl-C(═O)—, C₁₋₄(halo)alkyl-S(O)₀₋₂—, C₁₋₄ (halo)alkyl-C(═O)N(H)—, C₁₋₄(halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)₂N—C(═O)—, C₁₋₄(halo)alkyl-OC(═O)N(H)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—,(halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylamino, C₁₋₄dialkylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxy, C₂₋₅ heterocycloalkoxyand tetrahydronaphthalene.

E4 A compound of any one of E1-E3, wherein the compound has the formulaI-I, I-II, or I-III:

E5 A compound of E1, E2, E3, or E4 wherein B is N and R³ is absent.

E6 A compound of E1, E2, E3, or E4 wherein B is C.

E7 A compound of E1, E2, E3 E4, E5, or E6 wherein R², R³ and R⁴ are eachindependently selected from H, F, or Cl.

E8 A compound of E1, E2, E3 E4, E5, E6, E7, or E8 wherein R² is H, F orCl; R³ and R⁴ are each H; and R⁵ is an optionally substituted groupselected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈ alkyl,C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, and C₁₋₈ alkoxy.

E9 A compound of E1, E2, E3 E4, E5, E6, E7, or E8 wherein R¹ is C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₁₀ cycloalkyl or —NR^(1A)R^(1B).

E10 A compound of E9, wherein R¹ is selected from the group consistingof methyl, ethyl, propyl, trifluoromethyl, difluoromethyl,monofluoromethyl, isopropyl and cyclopropyl.

E11 A compound of E1, E2, E3 E4, E5, E6, E7, or E8 wherein R¹ isselected from the group consisting of:

E12 A compound of E1, E2, E3 E4, E5, E6, E7, or E8 wherein R¹ isselected from the group consisting of: methyl, ethyl, tert-butyl,dimethylamino, methylamino, amino, morpholino, azetidino, imidazolyl,3-hydroxyazetidino, 3-fluoroazetidino, cyclopropyl, pyrrolidinyl,3,3-difluoroazetidino, tert-butyl, ethyl, 2-methoxyethyl,3-methoxyazetidino, 2-hydroxyethyl, 3-hydroxypyrrolidinyl,N-methylimidazolyl, tetrahydrorofuranyl, 2-isopropoxyethyl,3-cyanoazetidino, 2-ethoxyethyl, 2-methoxypropyl, 2-hydroxypropyl,4-hydroxypiperidinyl and 3-methoxypyrrolidinyl and the followingformulas:

E13 A compound of E1, E2, E3 E4, E5, E6, E7, or E8 wherein R¹ isselected from the group consisting of: methyl, ethyl, tert-butyl,dimethylamino, methylamino, amino, morpholino, azetidino, imidazolyl,3-hydroxyazetidino, 3-fluoroazetidino, cyclopropyl, pyrrolidinyl,3,3-difluoroazetidino, tert-butyl, ethyl, 2-methoxyethyl,3-methoxyazetidino, 2-hydroxyethyl, 3-hydroxypyrrolidinyl, andN-methylimidazolyl.

E14 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, orE13 wherein X¹ is —O— or —N(H)—; X² is absent; the subscript m is 1; and-(L)- is an optionally substituted group selected from the groupconsisting of C₁₋₄ alkylene, C₂₋₄ alkenylene or C₂₋₄ alkynylene.

E15 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, orE13 wherein X¹ is —O— or —N(H)—; X² is absent; the subscript m is 1; and-(L)- is selected from the group consisting of —CH₂—, —C(═O)—,—C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—, —C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—,—CH₂—C(H)(CH₃)—CH₂— or —CH₂CH₂CH₂CH₂—.

E16 A compound of E15, wherein X¹ is —O—; the subscript m is 1 and -(L)-is —CH₂— or —CH₂—CH₂—.

E17 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,or E13 wherein X¹ is absent; X² is —O— or —N(H)—; the subscript m is 1;and -(L)- is selected from the group consisting of —C(H)₂—, —C(═O)—,—C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—, —C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—,—CH₂—C(H)(CH₃)—CH₂— or —CH₂CH₂CH₂CH₂—.

E18 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, orE13 wherein X¹ and X² is absent; the subscript m is 1; and -(L)- isselected from the group consisting of —C(H)₂—, —C(═O)—, —C(H)(CH₃)—,—CH₂—CH₂—, —CH₂—C(H)(CH₃)—, —C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—,—CH₂—C(H)(CH₃)—CH₂— or —CH₂CH₂CH₂CH₂—.

E19 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, orE13 wherein X¹ and

X² is absent; the subscript m is 1; and -(L)- is an optionallysubstituted C₁₋₄ heteroalkylene.

E20 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E1, E12, orE13 wherein m is 0; X¹ is selected from —O—, and —N(H)—; and X² isabsent.

E21 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, or E20 wherein A is an optionallysubstituted ring selected from the group consisting of cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, adamantane,bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane,bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[4.1.1]octane,bicyclo[3.3.1]nonane and 1,2,3,4-tetrahydro-1,4-methanonaphthalene,1,2,3,4-tetrahydroisoquinoline and chroman.

E22 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, or E20 wherein ring A is anoptionally substituted ring selected from the group consisting ofcyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane,cubane, bicyclo[2.2.2]octane, bicyclo[3.1.1]heptane,bicyclo[2.2.1]heptane, piperidinyl, tetrahydrofuranyl,tetrahydronaphthyl, spiro[2,5]octanyl, norpinanyl, spiro[3.5]nonanyl,8-azabicyclo[3.2.1]octanyl, norbornanyl, spiro[4.5]decanyl,bicyclo[4.1.0]heptane and spiro[5.5]undecanyl.

E23 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, or E20 wherein ring A is anoptionally substituted ring selected from the group consisting ofazetidine, pyrrolidine, piperidine, homopiperidine,(1R,5S)-8-azabicyclo[3.2.1]octane, 3-oxa-9-azabicyclo[3.3.1]nonane,(1s,4s)-7-azabicyclo[2.2.1]heptane, (1R,4S)-5-azabicyclo[2.1.1]hexane,7-(trifluoromethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine andquinuclidine.

E24 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, or E20 wherein ring A-(R^(A))_(n) isselected from the group consisting of

E25 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, or E20 wherein A-(R^(A))_(n) isselected from the group consisting of

E26 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, orE13 wherein the group:

is selected from the group consisting of

E27 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E19, or E20 wherein A is selected from thegroup consisting of

E28 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E20, E21, E22, or E23 wherein R^(A) isselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₅cycloalkyl, C₂₋₄ heterocycloalkyl, F, Cl, Br, I, —OH, —NH₂, —CN, —NO₂,C₁₋₄ alkoxy, —C(═O)—N(R^(A1))(R^(A2)) and —N(R^(A1))(R^(A2)).

E29 A compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,E13, E14, E15, E16, E17, E18, E20, E21, E22, or E23 wherein R^(A) ismethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, ethyl,pentafluoroethyl, cyclopropyl, —F, Cl, —OH, —NH₂ or —CN.

E30 A compound of E1, E2, E3, E4, E7, E8, E9, E10, E11, E12, E13, E14,E15, E16, E17, E18, E20, E21, E22, E23, E24, E25, E26, E27, E28, or E29wherein B is C; R³ is H, R² is F, Cl, Br, or I; R⁴ is H; and R⁵ is C₃₋₈cycloalkyl, wherein said C₃₋₈ cycloalkyl is further optionallysubstituted with from 1 to 3 R^(5a) substituents selected from F, Cl,Br, I, —OH, ═O, C₃₋₆ cycloalkyl, —CN, C₁₋₄ alkyl, —C₁₋₄ alkyl-O—C₁₋₄alkyl, C₁₋₄ haloalkyl and C₁₋₄ alkoxy.

E31 A compound of E30 wherein R⁵ is C₃₋₈ cycloalkyl.

E32 A compound of E1, E2, E3, E4, E21, E22, E23, E24, E25, E27, E28, orE29 wherein the group:

is selected from the group consisting of

E33 A compound of E1, E2, E3, E9, E10, E11, E12, E13, E14, E15, E16,E17, E18, E20, E21, E22, or E23 wherein the group:

is selected from the group consisting of

E34 A compound of E1 selected from the group consisting of compounds setforth in Table 1 presented herein.

In another aspect the present invention provides for a pharmaceuticalcomposition comprising compounds of formula I or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect of the invention, the present invention provides for amethod of treating a disease or condition in a mammal selected from thegroup consisting of pain, depression, cardiovascular diseases,respiratory diseases, and psychiatric diseases, and combinationsthereof, Such disesase or conditions can include neuropathic pain,inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumapain, surgical pain, post-surgical pain, childbirth pain, labor pain,neurogenic bladder, ulcerative colitis, chronic pain, persistent pain,peripherally mediated pain, centrally mediated pain, chronic headache,migraine headache, sinus headache, tension headache, phantom limb pain,dental pain, peripheral nerve injury or a combination thereof. Suchdisease or condition can include pain associated with HIV, HIV treatmentinduced neuropathy, trigeminal neuralgia, post-herpetic neuralgia,eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome,Crohns disease, pain associated with multiple sclerosis (MS),amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheralneuropathy, arthritis, rheumatoid arthritis, osteoarthritis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,malignant hyperthermia, cystic fibrosis, pseudoaldosteronism,rhabdomyolysis, hypothyroidism, bipolar depression, anxiety,schizophrenia, sodium channel toxi related illnesses, familialerythromelalgia, primary erythromelalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscause by stroke or neural trauma, tach-arrhythmias, atrial fibrillationand ventricular fibrillation.

In another aspect of the invention, the present invention provides for amethod of treating pain in a mammal by the inhibition of ion fluxthrough a voltage-dependent sodium channel in the mammal, wherein themethod comprises administring to the mammal in need thereof atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof.

In another aspect of the invention, the present invention provides for amethod of decreasing ion flux through a voltage-dependent sodium channelin a cell in a mammal, wherein the method comprises contacting the cellwith a compound of Formula I or a pharmaceutically acceptable saltthereof.

In another aspect of the invention, the present invention provides for amethod of treating pruritus in a mammal, wherein the method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof.

In another aspect of the invention, the present invention provides for amethod of treating cancer in a mammal, wherein the method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof.

In another aspect of the invention, the present invention provides for amethod of treating, but not preventing, pain in a mammal, wherein themethod comprises administering to the mammal in need thereof atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof. In such method, pain caninclude of neuropathic pain, inflammatory pain, visceral pain, cancerpain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain,childbirth pain, labor pain, neurogenic bladder, ulcerative colitis,chronic pain, persistent pain, peripherally mediated pain, centrallymediated pain, chronic headache, migraine headache, sinus headache,tension headache, phantom limb pain, dental pain, peripheral nerveinjury or a combination thereof. In such methods, pain can include painis associated with a disease or condition selected from the groupconsisting of HIV, HIV treatment induced neuropathy, trigeminalneuralgia, post-herpetic neuralgia, eudynia, heat sensitivity,tosarcoidosis, irritable bowel syndrome, Crohns disease, pain associatedwith multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS),diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoidarthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia,myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis,pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression,anxiety, schizophrenia, sodium channel toxi related illnesses, familialerythromelalgia, primary erythromelalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscause by stroke or neural trauma, tach-arrhythmias, atrial fibrillationand ventricular fibrillation.

In another aspect of the invention, the present invention provides for amethod for the treatment or prophylaxis of pain, depression,cardiovascular diseases, respiratory diseases, and psychiatric diseases,and combinations thereof, which method comprises administering aneffective amount of a Formula I or a pharmaceutically acceptable saltthereof.

In another aspect of the invention, the present invention provides for acompound of formula I or a pharmaceutically acceptable salt thereof forthe use as a medicament for the treatment of diseases and disordersselected from the group consisting of pain, depression, cardiovasculardiseases, respiratory diseases, and psychiatric diseases, or acombination thereof.

In another aspect of the invention, the present invention provides forthe use of a compound of any of formula I or a pharmaceuticallyacceptable salt thereof for the manufacture of a medicament for thetreatment of diseases and disorders selected from the group consistingof pain, depression, cardiovascular diseases, respiratory diseases, andpsychiatric diseases, or a combination thereof.

In another aspect of the invention, the present invention provides for acompound of Formula I or a pharmaceutically acceptable salt thereof forthe prophylactic or therapeutic treatment of pain, depression,cardiovascular disease, respiratory disease, or psychiatric disease.

In another aspect of the invention, the present invention provides for acompound of Formula I or a pharmaceutically acceptable salt thereof foruse in medical therapy.

In one aspect the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof with enhanced Nav1.7 potency.In another aspect the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof with reduced plasma proteininteractions. In another aspect the invention provides a compound offormula (I) or a pharmaceutically acceptable salt thereof with enhancedNav1.7 potency without significantly reduced plasma proteininteractions. For example, representative compounds of formula (I)wherein B is C; R³ is H, R² is F, Cl, Br, or I; and R⁵ is C₃₋₈cycloalkyl were found to possess enhanced Nav1.7 potency over similarcompounds wherein R⁵ is other than C₃₋₈ cycloalkyl.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the term “alkyl”, by itself or as part of anothersubstituent, means, unless otherwise stated, a straight or branchedchain hydrocarbon radical, having the number of carbon atoms designated(i.e., C₁₋₈ means one to eight carbons). Examples of alkyl groupsinclude methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl,iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and thelike. The term “alkenyl” refers to an unsaturated alkyl radical havingone or more double bonds. Similarly, the term “alkynyl” refers to anunsaturated alkyl radical having one or more triple bonds. Examples ofsuch unsaturated alkyl groups include vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers. The term “cycloalkyl,” “carbocyclic,” or “carbocycle” refers tohydrocarbon ringsystem having 3 to 10 overall number of ring atoms(e.g., 3-10 membered cycloalkyl is a cycloalkyl with 3 to 10 ring atoms,or C₃₋₁₀ cycloalkyl is a cycloalkyl with 3-10 carbon ring atoms) and fora 3-5 membered cycloalkyl being fully saturated or having no more thanone double bond between ring vertices and for a 6 membered cycloalkyl orlarger being fully saturated or having no more than two double bondsbetween ring vertices. As used herein, “cycloalkyl,” “carbocyclic,” or“carbocycle” is also meant to refer to bicyclic, polycyclic andspirocyclic hydrocarbon ring system, such as, for example,bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane,norborene, spirocyclic C₅₋₁₂ alkane, etc. As used herein, the terms,“alkenyl,” “alkynyl,” “cycloalkyl,”, “carbocycle,” and “carbocyclic,”are meant to include mono and polyhalogenated variants thereof.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chainhydrocarbon radical, consisting of the stated number of carbon atoms andfrom one to three heteroatoms selected from the group consisting of O,N, Si and S, and wherein the nitrogen and sulfur atoms can optionally beoxidized and the nitrogen heteroatom can optionally be quaternized. Theheteroatom(s) O, N and S can be placed at any interior position of theheteroalkyl group. The heteroatom Si can be placed at any position ofthe heteroalkyl group, including the position at which the alkyl groupis attached to the remainder of the molecule. A “heteroalkyl” cancontain up to three units of unsaturation, and also include mono- andpoly-halogenated variants, or combinations thereof. Examples include—CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—CF₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH═N(CH₃)—CH₃. Up to two heteroatoms can beconsecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.

The term “heterocycloalkyl,” “heterocyclic,” or “heterocycle” refers toa saturated or partially unsaturated ring system radical having theoverall having from 3-10 ring atoms (e.g., 3-10 memberedheterocycloalkyl is a heterocycloalkyl radical with 3-10 ring atoms, aC₂₋₉ heterocycloalkyl is a heterocycloalkyl having 3-10 ring atoms withbetween 2-9 ring atoms being carbon) that contain from one to fiveheteroatoms selected from N, O, and S, wherein the nitrogen and sulfuratoms are optionally oxidized, nitrogen atom(s) are optionallyquaternized, as ring atoms. Unless otherwise stated, a“heterocycloalkyl,” “heterocyclic,” or “heterocycle” ring can be amonocyclic, a bicyclic, spirocyclic or a polycylic ring system. Nonlimiting examples of “heterocycloalkyl,” “heterocyclic,” or“heterocycle” rings include pyrrolidine, piperidine, N-methylpiperidine,imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine,pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine,thiomorpholine-5-oxide, thiomorpholine-S,S-oxide, piperazine, pyran,pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran,tetrhydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane,(1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane,(1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and the like A“heterocycloalkyl,” “heterocyclic,” or “heterocycle” group can beattached to the remainder of the molecule through one or more ringcarbons or heteroatoms. A “heterocycloalkyl,” “heterocyclic,” or“heterocycle” can include mono- and poly-halogenated variants thereof.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane (including branched alkane), asexemplified by —CH₂CH₂CH₂CH₂— and —CH(CH₂)CH₂CH₂—. Typically, an alkyl(or alkylene) group will have from 1 to 24 carbon atoms, with thosegroups having 10 or fewer carbon atoms being preferred in the presentinvention. “Alkenylene” and “alkynylene” refer to the unsaturated formsof “alkylene” having double or triple bonds, respectively. “Alkylene”,“alkenylene” and “alkynylene” are also meant to include mono andpoly-halogenated variants.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical, saturated or unsaturated or polyunsaturated,derived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—, —O—CH₂—CH═CH—, —CH₂—CH═C(H)CH₂—O—CH₂— and—S—CH₂—C≡C—. For heteroalkylene groups, heteroatoms can also occupyeither or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,alkyleneamino, alkylenediamino, and the like). The term “heteroalkylene”is also meant to include mono and poly-halogenated variants.

The terms “alkoxy,” “alkylamino” and “alkylthio”, are used in theirconventional sense, and refer to those alkyl groups attached to theremainder of the molecule via an oxygen atom (“oxy”), an amino group(“amino”) or thio group, and further include mono- and poly-halogenatedvariants thereof. Additionally, for dialkylamino groups, the alkylportions can be the same or different.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. The term “(halo)alkyl” is meant to include botha “alkyl” and “haloalkyl” substituent. Additionally, the term“haloalkyl,” is meant to include monohaloalkyl and polyhaloalkyl. Forexample, the term “C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon ring radical, which can be a single ringor multiple rings (up to three rings) which are fused together andhaving the stated number of aryl ring atoms. The term “heteroaryl”refers to aryl ring(s) that contain from one to five heteroatomsselected from N, O, and S, wherein the nitrogen and sulfur atoms areoptionally oxidized, and the nitrogen atom(s) are optionallyquaternized. A heteroaryl group can be attached to the remainder of themolecule through a heteroatom. Non-limiting examples of aryl groupsinclude phenyl, naphthyl and biphenyl, while non-limiting examples ofheteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl,triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl,benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,pyrrolyl, thiazolyl, furyl, thienyl and the like. Optional substituentsfor each of the above noted aryl and heteroaryl ring systems can beselected from the group of acceptable substituents described furtherbelow.

The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in someembodiments, will include both substituted and unsubstituted forms ofthe indicated radical. Preferred substituents for each type of radicalare provided below.

Substituents for the alkyl radicals (including those groups oftenreferred to as alkylene, alkenyl, alkynyl, heteroalkyl, cycloalkyl andheterocycloalkyl) can be a variety of groups including, but not limitedto, -halogen, —OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′″C(O)NR′R″, —NR″C(O)₂R′,—NHC(NH₂)═NH, —NRC(NH₂)═NH, —NHC(NH₂)═NR′, —NR′″C(NR′R″)═N—CN,—NR′″C(NR′R″)═NOR′, —NHC(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NR′S(O)₂R″, —NR′″S(O)₂NR′R″, —CN, —NO₂, —(CH₂)₁₋₄—OR′, —(CH₂)₁₋₄—NR′R″,—(CH₂)₁₋₄—SR′, —(CH₂)₁₋₄—SiR′R″R′″, —(CH₂)₁₋₄—OC(O)R′, —(CH₂)₁₋₄—C(O)R′,—(CH₂)₁₋₄—CO₂R′, —(CH₂)₁₋₄CONR′R″, in a number ranging from zero to(2m′+1), where m′ is the total number of carbon atoms in such radical.R′, R″ and R′″ each independently refer groups including, for example,hydrogen, unsubstituted C₁₋₆ alkyl, unsubstituted heteroalkyl,unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstitutedC₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₆ thioalkoxy groups, or unsubstitutedaryl-C₁₋₄ alkyl groups, unsubstituted heteroaryl, substitutedheteroaryl, among others. When R′ and R″ are attached to the samenitrogen atom, they can be combined with the nitrogen atom to form a 3-,4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include1-pyrrolidinyl and 4-morpholinyl. Other substitutents for alkylradicals, including heteroalkyl, alkylene, include for example, ═O,═NR′, ═N—OR′, ═N—CN, ═NH, wherein R¹ include substituents as describedabove.

Similarly, substituents for the aryl and heteroaryl groups are variedand are generally selected from the group including, but not limited to,-halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′,—CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′, —NR′C(O)NR″R′″,—NHC(NH₂)═NH, —NR′C(NH₂)═NH, —NHC(NH₂)═NR′, —S(O) R′, —S(O)₂R′,—S(O)₂NR′R″, —NR′S(O)₂R″, —N₃, perfluoro-C₁₋₄ alkoxy, and perfluoro-C₁₋₄alkyl, —(CH₂)₁₋₄—OR′, —(CH₂)₁₋₄—NR′R″, —(CH₂)₁₋₄—SR′,—(CH₂)₁₋₄—SiR′R″R′″, —(CH₂)₁₋₄—OC(O)R′, —(CH₂)₁₋₄—C (O)R′,—(CH₂)₁₋₄—CO₂R′, —(CH₂)₁₋₄CONR′R″, in a number ranging from zero to thetotal number of open valences on the aromatic ring system; and where R′,R″ and R′″ are independently selected from hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, unsubstituted aryl andheteroaryl, (unsubstituted aryl)-C₁₋₄ alkyl, and unsubstitutedaryloxy-C₁₋₄ alkyl. Other suitable substituents include each of theabove aryl substituents attached to a ring atom by an alkylene tether offrom 1-4 carbon atoms. When a substituent for the aryl or heteroarylgroup contains an alkylene linker (e.g., —(CH₂)₁₋₄—NR′R″), the alkylenelinker includes halo variants as well. For example, the linker“˜(CH₂)₁₋₄-” when used as part of a substituent is meant to includedifluoromethylene, 1,2-difluoroethylene, etc.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

As used herein, the term “chiral” refers to molecules which have theproperty of non-superimposability of the mirror image partner, while theterm “achiral” refers to molecules which are superimposable on theirmirror image partner.

As used herein, the term “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicates the point ofattachment of the bond that the wavy bond intersects in the chemicalstructure to the remainder of a molecule.

As used herein, the term “C-linked” means that the group that the termdescribes is attached the remainder of the molecule through a ringcarbon atom.

As used herein, the term “N-linked” means that the group that the termdescribes is attached to the remainder of the molecule through a ringnitrogen atom.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers can separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention can contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer can also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which canoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

As used herein, the term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

As used herein, the term “solvate” refers to an association or complexof one or more solvent molecules and a compound of the invention.Examples of solvents that form solvates include, but are not limited to,water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,and ethanolamine. The term “hydrate” refers to the complex where thesolvent molecule is water.

As used herein, the term “protecting group” refers to a substituent thatis commonly employed to block or protect a particular functional groupon a compound. For example, an “amino-protecting group” is a substituentattached to an amino group that blocks or protects the aminofunctionality in the compound. Suitable amino-protecting groups includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ)and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitable protectinggroups include acetyl and silyl. A “carboxy-protecting group” refers toa substituent of the carboxy group that blocks or protects the carboxyfunctionality. Common carboxy-protecting groups includephenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyland the like. For a general description of protecting groups and theiruse, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups inOrganic Synthesis 4^(th) edition, Wiley-Interscience, New York, 2006.

As used herein, the term “mammal” includes, but is not limited to,humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows,pigs, and sheep

As used herein, the term “pharmaceutically acceptable salts” is meant toinclude salts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic functionalities, base addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al., “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds can be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. As used herein the term “prodrug” refers tothose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Prodrugs of the invention include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues, is covalently joined through an amide orester bond to a free amino, hydroxy or carboxylic acid group of acompound of the present invention. The amino acid residues include butare not limited to the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also includes phosphoserine,phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine,demosine, isodemosine, gamma-carboxyglutamate, hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, citrulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine, phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention can be derivatized as anamide or alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups can be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁₋₆)alkanoyloxymethyl,1-((C₁₋₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁₋₆)alkanoyloxy)ethyl,(C₁₋₆)alkoxycarbonyloxymethyl, N—(C₁₋₆)alkoxycarbonylaminomethyl,succinoyl, (C₁₋₆)alkanoyl, alpha-amino(C₁₋₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

Additionally, the present invention provides for metabolites ofcompounds of the invention. As used herein, a “metabolite” refers to aproduct produced through metabolism in the body of a specified compoundor salt thereof. Such products can result for example from theoxidation, reduction, hydrolysis, amidation, deamidation,esterification, deesterification, enzymatic cleavage, and the like, ofthe administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention can exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention.

The compounds of the present invention can also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the present invention alsoembraces isotopically-labeled variants of the present invention whichare identical to those recited herein, but the for the fact that one ormore atoms are replace by an atom having the atomic mass or mass numberdifferent from the predominant atomic mass or mass number usually foundin nature for the atom. All isotopes of any particular atom or elementas specified are contemplated within the scope of the compounds of theinvention, and their uses. Exemplary isotopes that can be incorporatedin to compounds of the invention include istopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine,such as ²H (“D”), ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P,³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Certain isotopically labeled compounds ofthe present invention (e.g., those labeled with ³H or ¹⁴C) are useful incompound and/or substrate tissue distribution assays. Tritiated (³H) andcarbon-14 (¹⁴C) isotopes are useful for their ease of preparation anddetectability. Further substituteion with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resutingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸Fare useful for positron emission tomography (PET) studies to examinesubstrate receptor occupancy. Isotopically labeled compounds of thepresent inventions can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and/or in the Examplesherein below, by substituting an isotopically labeled reagent for anon-isotopically labeled reagent.

The terms “treat” and “treatment” refer to both therapeutic treatmentand/or prophylactic treatment or preventative measures, wherein theobject is to prevent or slow down (lessen) an undesired physiologicalchange or disorder, such as, for example, the development or spread ofcancer. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease or disorder, stabilized (i.e., notworsening) state of disease or disorder, delay or slowing of diseaseprogression, amelioration or palliation of the disease state ordisorder, and remission (whether partial or total), whether detectableor undetectable. “Treatment” can also mean prolonging survival ascompared to expected survival if not receiving treatment. Those in needof treatment include those already with the disease or disorder as wellas those prone to have the disease or disorder or those in which thedisease or disorder is to be prevented.

The phrase “therapeutically effective amount” or “effective amount”means an amount of a compound of the present invention that (i) treatsor prevents the particular disease, condition, or disorder, (ii)attenuates, ameliorates, or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevents or delaysthe onset of one or more symptoms of the particular disease, condition,or disorder described herein. For cancer therapy, efficacy can, forexample, be measured by assessing the time to disease progression (TTP)and/or determining the response rate (RR).

The term “bioavailability” refers to the systemic availability (i.e.,blood/plasma levels) of a given amount of drug administered to apatient. Bioavailability is an absolute term that indicates measurementof both the time (rate) and total amount (extent) of drug that reachesthe general circulation from an administered dosage form.

A. Compounds

In one aspect the present invention provides for compounds of Formula I:

and pharmaceutically acceptable salts thereof, wherein in Formula I:

R¹ is C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₁₂ cycloalkyl,C-linked C₂₋₁₁ heterocycloalkyl, heteroaryl, or —NR^(1A)R^(1B), whereinR^(1A) and R^(1B) are each independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, C₁₋₈ alkoxy, (6-10 memberedaryl)-(X^(R1))₀₋₁—, (5-10 membered heteroaryl)-(X^(R1))₀₋₁—, and whereinR^(1A) and R^(1B) are optionally combined to form a 3 to 9 memberedheterocyclic ring optionally comprising 1 additional heteroatom selectedfrom N, O and S and optionally fused thereto is a benzene or pyridinering; X^(R1) is selected from the group consisting of C₁₋₄ alkylene,C₁₋₄ heteroalkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene; and wherein thealiphatic and aromatic portions of R¹ are optionally substituted withfrom 1 to 5 R^(R1) substituents selected from the group consisting ofC₁₋₈ alkyl, C₁₋₈ haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂, ═O,—(X^(1R))₀₋₁NR^(R1a)R^(R1b), —(X^(1R))₀₋₁OR^(R1a), —(X^(1R))₀₋₁SR^(R1a),—(X^(1R))₀₋₁N(R^(R1a))C(═O)OR^(R1c),—(X^(1R))₀₋₁C(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))C(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁C(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))C(═O)R^(R1b), —(X^(1R))₀₋₁C(═O)OR^(R1a),—(X^(1R))₀₋₁OC(═O)R^(R1a), —(X^(1R))₀₋₁—P(═O)(OR^(R1a))(OR^(R1b)),—(X^(1R))₀₋₁S(O)₁₋₂R^(R1c), —(X^(1R))₀₋₁—S(O)₁₋₂N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))S(O)₁₋₂N(R^(R1a))(R^(R1b)) and—(X^(1R))₀₋₁N(R^(R1a))S(O)₁₋₂(R^(R1c)), wherein X^(1R) is selected fromthe group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein R^(R1a) and R^(R1b) areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, heteroaryl, andC₂₋₇ heterocycloalkyl; R^(R1c) is selected from the group consisting ofC₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, heteroaryl,and C₂₋₇ heterocycloalkyl;

R^(N) is hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

B is C or N;

R², R³ and R⁴ are each independently selected from the group consistingof H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy, andR³ is absent when B is nitrogen;

R⁵ is selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₈ cycloalkyl, C₂₋₇heterocycloalkyl, phenyl and 5-6 membered heteroaryl comprising 1 to 3heteroatoms selected from N, O and S, wherein said 5-6 memberedheteroaryl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl or C₂₋₇ heterocycloalkyl isfurther optionally substituted with from 1 to 3 R^(5a) substituentsselected from F, Cl, Br, I, —OH, ═O, C₃₋₆ cycloalkyl, —CN, C₁₋₄ alkyl,—C₁₋₄ alkyl-O—C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ alkoxy;

L is a linker selected from the group consisting of C₁₋₄ alkylene, C₂₋₄alkenylene, C₂₋₄ alkynylene, and C₁₋₄ heteroalkylene, wherein L isoptionally substituted with from 1 to 3 R^(L) substituents selected fromthe group consisting of ═O, —OH, —OCH2.phenyl, C₁₋₄ alkyl, C₁₋₄haloalkyl and C₁₋₄ acyl;

the subscript m represents the integer 0 or 1;

X¹ and X² are each independently selected from the group consisting ofabsent, —O—, —S(O)—, —S(O)₂— and —N(R^(X))— wherein R^(x) is H, C₁₋₈alkyl, C₁₋₈ acyl or —S(O)₂(C₁₋₈ alkyl), and wherein if the subscript mis 0 then at least one of X¹ or X² is absent;

the subscript n is an integer from 0 to 5;

A is selected from the group consisting of hydrogen, C₃₋₁₂ cycloalkyl,C₂₋₁₁ heterocycloalkyl, phenyl having a 3-8 membered carbocyclic orheterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and Sfused thereto or a 5 to 6 membered heteroaryl having a 3-8 memberedcarbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selectedfrom N, O and S fused thereto, and wherein if A is hydrogen then thesubscript n is 0; and

R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₃₋₈cycloalkyl, C₁₋₈ haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂, ═O,heteroaryl, —(X^(RA))₀₋₁NR^(A1)R^(A2), —(X^(RA))₀₋₁OR^(A1),—(X^(RA))₀₋₁SR^(A1), —(X^(RA))₀₋₁N(R^(A1))C(═O)OR^(A3),—(X^(RA))₀₋₁OC(═O)N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁N(R^(A1))C(═O)N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)), —(X^(RA))₀₋₁N(R^(A1))C(═O)R^(A2),—(X^(RA))₀₋₁C(═O)OR^(A1), —(X^(RA))₀₋₁OC(═O)R^(A1),—P(═O)(OR^(A1))(OR^(A2)), —(X^(RA))₀₋₁S(O)₁₋₂R^(A3),—(X^(RA))₀₋₁S(O)₁₋₂N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)) and—(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂(R^(A3)), wherein X^(RA) is selected fromthe group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein R^(A1) and R^(A2) areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl,tetrahydronapthalene, phenyl, benzyl, heteroaryl, and C₂₋₇heterocycloalkyl; R^(A3) is selected from the group consisting of C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, tetrahydronapthalene, phenyl,benzyl, heteroaryl, and C₂₋₇ heterocycloalkyl; wherein if A is amonocyclic C₃₋₁₂ carbocycloalkyl or monocyclic C₂₋₁₁ heterocycloalkyl,then any two R^(A) substituents attached to adjacent atoms on the A ringare optionally combined to form a benzene or a 5 to 6 memberedheteroaryl ring; and wherein the aliphatic and aromatic portions of aR^(A) substitutent is optionally substituted with from 1 to 5 R^(RA)substitutents selected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ (halo)alkyl-C(═O)—, C₁₋₄(halo)alkyl-S(O)₀₋₂—, C₁₋₄ (halo)alkyl-C(═O)N(H)—, C₁₋₄(halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)₂N—C(═O)—, C₁₋₄(halo)alkyl-OC(═O)N(H)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—,(halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylamino, C₁₋₄dialkylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxy, C₂₋₅ heterocycloalkoxy,tetrahydronaphthalene and phenyl wherein phenyl is optionallysubstituted with 1-3 fluoro, chloro, bromo, CN, C₁₋₄ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ ordialkylamino;

with the proviso that a compound of Formula I is not

-   4-(cyclohexylmethoxy)-N-(methylsulfonyl)benzamide;-   4-(cyclopentylmethoxy)-N-(methylsulfonyl)benzamide or-   4-(cyclobutylmethoxy)-2,5-difluoro-N-(methylsulfonyl)benzamide.

In another aspect the present invention provides for a compound offormula (I) and pharmaceutically acceptable salts thereof, wherein inFormula I:

R¹ is C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₁₂ cycloalkyl,C-linked C₂₋₁₁ heterocycloalkyl, heteroaryl, or —NR^(1A)R^(1B), whereinR^(1A) and R^(1B) are each independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, C₁₋₈ alkoxy, (6-10 memberedaryl)-(X^(R1))₀₋₁—, (5-10 membered heteroaryl)-(X^(R1))₀₋—, and whereinR^(1A) and R^(1B) are optionally combined to form a 3 to 8 memberedheterocyclic ring optionally comprising 1 additional heteroatom selectedfrom N, O and S as ring vertex and optionally fused thereto is a benzeneor pyridine ring; X^(R1) is selected from the group consisting of C₁₋₄alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene; andwherein the aliphatic and aromatic portions of R¹ are optionallysubstituted with from 1 to 5 R^(R1) substituents selected from the groupconsisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂,═O, —(X^(1R))₀₋₁NR^(R1a)R^(R1b), —(X^(1R))₀₋₁OR^(R1a),—(X^(1R))₀₋₁SR^(R1a), —(X^(1R))₀₋₁N(R^(R1a))C(═O)OR^(R1c),—(X^(1R))₀₋₁C(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))C(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁C(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))C(═O)R^(R1b), —(X^(1R))₀₋₁C(═O)OR^(R1a),—(X^(1R))₀₋₁OC(═O)R^(R1a), —(X^(1R))₀₋₁—P(═O)(OR^(R1a))(OR^(R1b)),—(X^(1R))₀₋₁S(O)₁₋₂R^(R1c), —(X^(1R))₀₋₁S(O)₁₋₂N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))S(O)₁₋₂N(R^(R1a))(R^(R1b)) and—(X^(1R))₀₋₁N(R^(R1a))S(O)₁₋₂(R^(R1c)), wherein X^(1R) is selected fromthe group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein R^(R1a) and R^(R1b) areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, heteroaryl, andC₂₋₇ heterocycloalkyl; R^(R1c) is selected from the group consisting ofC₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, heteroaryl,and C₂₋₇ heterocycloalkyl;

R^(N) is hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

B is C or N;

R², R³ and R⁴ are each independently selected from the group consistingof H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy, andR³ is absent when B is nitrogen;

R⁵ is selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₈ cycloalkyl, C₂₋₇heterocycloalkyl, phenyl and 5-6 membered heteroaryl comprising 1 to 3heteroatoms selected from N, O and S, wherein said 5-6 memberedheteroaryl is further optionally substituted with from 1 to 3 R⁵substituents selected from F, Cl, Br, I, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyland C₁₋₄ alkoxy;

L is a linker selected from the group consisting of C₁₋₄ alkylene, C₂₋₄alkenylene, C₂₋₄ alkynylene, and C₁₋₄ heteroalkylene, wherein L isoptionally substituted with from 1 to 3 R^(L) substituents selected fromthe group consisting of ═O, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ acyl;

the subscript m represents the integer 0 or 1;

X¹ and X² are each independently selected from the group consisting ofabsent, —O—, —S(O)—, —S(O)₂— and —N(R^(X))— wherein R^(x) is H, C₁₋₈alkyl, C₁₋₈ acyl or —S(O)₂(C₁₋₈ alkyl), and wherein if the subscript

m is 0 then one of X¹ or X² is absent;

the subscript n is an integer from 0 to 5;

A is selected from the group consisting of hydrogen, C₃₋₁₂ cycloalkyl,C₂₋₁₁ heterocycloalkyl, phenyl having a 3-8 membered carbocyclic orheterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and Sfused thereto or a 5 to 6 membered heteroaryl having a 3-8 memberedcarbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selectedfrom N, O and S fused thereto, and wherein if A is hydrogen then thesubscript n is 0; and

R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂, ═O, heteroaryl,—(X^(RA))₀₋₁NR^(A1)R^(A2), —(X^(RA))₀₋₁OR^(A1), —(X^(RA))₀₋₃SR^(A1),—(X^(RA))₀₋₁N(R^(A1))C(═O)OR^(A3), —(X^(RA))₀₋₁OC(═O)N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁N(R^(A1))C(═O)N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)), —(X^(RA))₀₋₁N(R^(A1))C(═O)R^(A2),—(X^(RA))₀₋₁C(═O)OR^(A1), —(X^(RA))₀₋₁OC(═O)R^(A1),—P(═O)(OR^(A1))(OR^(A2)), —(X^(RA))₀₋₁S(O)₁₋₂R^(A3),—(X^(RA))₀₋₁S(O)₁₋₂N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁N(R^(A1))S(O)₁₂N(R^(A1))(R^(A2)) and—(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂(R^(A3)), wherein X^(RA) is selected fromthe group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein R^(A1) and R^(A2) areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, tetrahydronapthalene, phenyl,benzyl, heteroaryl, and C₂₋₇ heterocycloalkyl; R^(A3) is selected fromthe group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl,tetrahydronapthalene, phenyl, benzyl, heteroaryl, and C₂₋₇heterocycloalkyl; wherein if A is a monocyclic C₃₋₁₂ carbocycloalkyl ormonocyclic C₂₋₁₁ heterocycloalkyl, then any two R^(A) substituentsattached to adjacent atoms on the A ring are optionally combined to forma benzene or a 5 to 6 membered heteroaryl ring; and wherein thealiphatic and aromatic portions of a R^(A) substitutent is optionallysubstituted with from 1 to 5 R^(RA) substitutents selected from, F, Cl,Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ (halo)alkyl-C(═O)—, C₁₋₄ (halo)alkyl-S(O)₀₋₂—, C₁₋₄(halo)alkyl-C(═O)N(H)—, C₁₋₄ (halo)alkyl-N(H)—C(═O)—,((halo)alkyl)₂N—C(═O)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—, C₁₋₄(halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—,((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylamino, C₁₋₄ dialkylamino, C₃₋₆cycloalkyl, C₃₋₆ cycloalkoxy, C₂₋₅ heterocycloalkoxy andtetrahydronaphthalene;

with the proviso that a compound of Formula I is not

-   4-(cyclohexylmethoxy)-N-(methylsulfonyl)benzamide;-   4-(cyclopentylmethoxy)-N-(methylsulfonyl)benzamide or-   4-(cyclobutylmethoxy)-2,5-difluoro-N-(methylsulfonyl)benzamide.

In another aspect the present invention provides for a compound offormula (I) and pharmaceutically acceptable salts thereof, wherein inFormula I:

R¹ is C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₁₂ cycloalkyl,C-linked C₂₋₁₁ heterocycloalkyl or —NR^(1A)R^(1B), wherein R^(1A) andR^(1B) are each independently selected from the group consisting ofhydrogen, C₁₋₈ alkyl, C₁₋₈ alkoxy, (6-10 membered aryl)-(X^(R1))₀₋₁—,(5-10 membered heteroaryl)-(X^(R1))₀₋₁—, and wherein R^(1A) and R^(1B)are optionally combined to form a 3 to 8 membered heterocyclic ringoptionally comprising 1 additional heteroatoms selected from N, O and Sas ring vertex and optionally fused thereto is a benzene or pyridinering; X^(R1) is selected from the group consisting of C₁₋₄ alkylene,C₁₋₄ heteroalkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene; and wherein thealiphatic and aromatic portions of R¹ are optionally substituted withfrom 1 to 5 R^(R1) substituents selected from the group consisting ofC₁₋₈ alkyl, C₁₋₈ haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂,—(X^(1R))₀₋₁—NR^(R1a)R^(R1b), —(X^(1R))₀₋₁OR^(R1a),—(X^(1R))₀₋₁SR^(R1a), —(X^(1R))₀₋₁N(R^(R1a))C(═O)OR^(R1c),—(X^(1R))₀₋₁OC(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))C(═O)N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁C(═O)N(R^(R1a))R^(R1b)), —(X^(1R))₀₋₁N(R^(R1a))C(═O)R^(R1b),—(X^(1R))₀₋₁C(═O)OR^(R1a), —(X^(1R))₀₋₁OC(═O)R^(R1a),—(X^(1R))₀₋₁—P(═O)(R^(R1a))(OR^(R1b)), —(X^(1R))₀₋₁S(O)₁₋₂R^(R1c),—(X^(1R))₀₋₁S(O)₁₋₂N(R^(R1a))(R^(R1b)),—(X^(1R))₀₋₁N(R^(R1a))S(O)₁₋₂N(R^(R1a))(R^(R1b)) and—(X^(1R))₀₋₁N(R^(R1a))S(O)₁₋₂(R^(R1c)), wherein X^(1R) is selected fromthe group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein R^(R1a) and R^(R1b) areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, C₅₋₆ heteroaryland C₂₋₇ heterocycloalkyl; R^(R1) is selected from the group consistingof C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, C₅₋₆heteroaryl and C₂₋₇ heterocycloalkyl;

R^(N) is hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

B is C or N;

R², R³ and R⁴ are each independently selected from the group consistingof H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy, andR³ is absent when B is nitrogen;

R⁵ is selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₈ cycloalkyl, C₂₋₇heterocycloalkyl, phenyl and 5-6 membered heteroaryl comprising 1 to 3heteroatoms selected from N, O and S, wherein said 5-6 memberedheteroaryl is further optionally substituted with from 1 to 3 R⁵substituents selected from F, Cl, Br, I, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyland C₁₋₄ alkoxy;

L is a linker selected from the group consisting of C₁₋₄ alkylene, C₂₋₄alkenylene, C₂₋₄ alkynylene, and C₁₋₄ heteroalkylene, wherein L isoptionally substituted with from 1 to 3 R^(L) substituents selected fromthe group consisting of ═O, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ acyl;

the subscript m represents the integer 0 or 1;

X¹ and X² are each independently selected from the group consisting ofabsent, —O—, —S(O)—, —S(O)₂— and —N(R^(X))— wherein R^(x) is C₁₋₈ alkyl,C₁₋₈ acyl or —S(O)₂(C₁₋₈ alkyl), and wherein if the subscript m is 0then one of X¹ or X² is absent;

the subscript n is an integer from 0 to 5;

A is selected from the group consisting of hydrogen, C₃₋₁₂ cycloalkyl,C₂₋₁₁ heterocycloalkyl, phenyl having a 3-8 membered carbocyclic orheterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and Sfused thereto or a 5 to 6 membered heteroaryl having a 3-8 memberedcarbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selectedfrom N, O and S fused thereto, and wherein if A is hydrogen then thesubscript n is 0; and

R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂, —(X^(RA))₀₋₁NR^(A1)R^(A2),—(X^(RA))₀₋₁OR^(A1), —(X^(RA))₀₋₁SR^(A1),—(X^(RA))₀₋₁N(R^(A1))C(═O)OR^(A3), —(X^(RA))₀₋₁OC(═O)N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁N(R^(A1))C(═O)N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)), —(X^(RA))₀₋₁N(R^(A1))C(═O)R^(A2),—(X^(RA))₀₋₁C(═O)OR^(A1), —(X^(RA))₀₋₁OC(═O)R^(A1),—P(═O)(OR^(A1))(R^(A2)), —(X^(RA))₀₋₁S(O)₁₋₂R^(A3),—(X^(RA))₀₋₁S(O)₁₋₂N(R^(A1))(R^(A2)),—(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)) and—(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂(R^(A3)), wherein X^(RA) is selected fromthe group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene; wherein R^(A1) and R^(A2) areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, tetrahydronapthalene, phenyl,benzyl, C₅₋₆ heteroaryl and C₂₋₇ heterocycloalkyl; R^(A3) is selectedfrom the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈cycloalkyl, tetrahydronapthalene, phenyl, benzyl, C₅₋₆ heteroaryl andC₂₋₇ heterocycloalkyl; wherein if A is a monocyclic C₃₋₁₂carbocycloalkyl or monocyclic C₂₋₁₁ heterocycloalkyl, then any two RAsubstituents attached to adjacent atoms on the A ring are optionallycombined to form a benzene or a 5 to 6 membered heteroaryl ring; andwherein the aliphatic and aromatic portions of a R^(A) substitutent isoptionally substituted with from 1 to 5 R^(RA) substitutents selectedfrom, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ (halo)alkyl-C(═O)—, C₁₋₄(halo)alkyl-S(O)₀₋₂—, C₁₋₄ (halo)alkyl-C(═O)N(H)—, C₁₋₄(halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)₂N—C(═O)—, C₁₋₄(halo)alkyl-OC(═O)N(H)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—,(halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylamino, C₁₋₄dialkylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxy, C₂₋₅ heterocycloalkoxyand tetrahydronaphthalene.

In another embodiment, a compound of formula I has the formula

In another embodiment, in compounds of formula I, B is N and R³ isabsent.

In another embodiment, in compounds of formula I, B is carbon.

In another embodiment, in compounds of formula I, R², R³ and R⁴ are eachindependently selected from H, F, or Cl.

In another embodiment, in compounds of formula I, R² is H, F or Cl; R³and R⁴ are each H; and R⁵ is an optionally substituted group selectedfrom the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₈ cycloalkyl, and C₁₋₈ alkoxy.

In another embodiment, in compounds of formula I, R² is H, F or Cl; R³and R⁴ are each H; and R⁵

is an optionally substituted group selected from the group consisting ofH, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl, and C₁₋₈ alkoxy.

In another embodiment, in compounds of formula I, R¹ is C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₁₀ cycloalkyl or —NR^(1A)R^(1B).

In another embodiment, in compounds of formula I, R¹ is selected fromthe group consisting of methyl, ethyl, propyl, trifluoromethyl,difluoromethyl, monofluoromethyl, isopropyl and cyclopropyl.

In another embodiment, in compounds of formula I, R¹ is selected fromthe group consisting of methyl, ethyl, propyl, trifluoromethyl,difluoromethyl, monofluoromethyl, isopropyl, cyclopropyl, pyrrolidinyl,3,3-difluoroazetidino, tert-butyl, ethyl, 2-methoxyethyl,3-methoxyazetidino, 2-hydroxyethyl, 3-hydroxypyrrolidinyl, andN-methylimidazolyl.

In another embodiment, in compounds of formula I, R¹ is selected fromthe group consisting of:

In another embodiment, in compounds of formula I, R¹ is selected fromthe group consisting of: methyl, ethyl, tert-butyl, dimethylamino,methylamino, amino, morpholino, azetidino, imidazolyl,3-hydroxyazetidino, 3-fluoroazetidino, cyclopropyl, pyrrolidinyl,3,3-difluoroazetidino, tert-butyl, ethyl, 2-methoxyethyl,3-methoxyazetidino, 2-hydroxyethyl, 3-hydroxypyrrolidinyl,N-methylimidazolyl, tetrahydrorofuranyl, 2-isopropoxyethyl,3-cyanoazetidino, 2-ethoxyethyl, 2-methoxypropyl, 2-hydroxypropyl,4-hydroxypiperidinyl and 3-methoxypyrrolidinyl and the followingformulas:

In another embodiment, in compounds of formula I, X¹ is —O— or —N(H)—;X² is absent; the subscript m is 1; and -(L)- is an optionallysubstituted group selected from the group consisting of C₁₋₄ alkylene,C₂₋₄ alkenylene or C₂₋₄ alkynylene.

In another embodiment, in compounds of formula I, X¹ is —O— or —N(H)—;X² is absent; the subscript m is 1; and -(L)- is selected from the groupconsisting of —CH₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—,—C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₃)—CH₂— or —CH₂CH₂CH₂CH₂—.

In another embodiment, in compounds of formula I, X¹ is —O—; thesubscript m is 1 and -(L)- is —CH₂— or —CH₂—CH₂—.

In another embodiment, in compounds of formula I, X¹ is absent; X² is—O— or —N(H)—; the subscript m is 1; and -(L)- is selected from thegroup consisting of —C(H)₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—,—CH₂—C(H)(CH₃)—, —C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₃)—CH₂— or—CH₂CH₂CH₂CH₂—.

In another embodiment, in compounds of formula I, X¹ and X² is absent;the subscript m is 1; and -(L)- is selected from the group consisting of—C(H)₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—,—C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₃)—CH₂— or —CH₂CH₂CH₂CH₂—.

In another embodiment, in compounds of formula I, X¹ and X² is absent;the subscript m is 1; and -(L)- is an optionally substituted C₁₋₄heteroalkylene.

In another embodiment, in compounds of formula I, m is 0; X¹ is selectedfrom —O—, and —N(H)—; and X² is absent.

In another embodiment, in compounds of formula I, A is an optionallysubstituted ring selected from the group consisting of cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, adamantane,bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane,bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[4.1.1]octane,bicyclo[3.3.1]nonane 1,2,3,4-tetrahydro-1,4-methanonaphthalene,1,2,3,4-tetrahydroisoquinoline and chroman.

In another embodiment, in compounds of formula I, ring A is anoptionally substituted ring selected from the group consisting ofcyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane,cubane, bicyclo[2.2.2]octane, bicyclo[3.1.1]heptane,bicyclo[2.2.1]heptane piperidinyl, tetrahydrofuranyl,tetrahydronaphthyl, spiro[2,5]octanyl, norpinanyl, spiro[3.5]nonanyl,8-azabicyclo[3.2.1]octanyl, norbornanyl, spiro[4.5]decanyl,bicyclo[4.1.0]heptane and spiro[5.5]undecanyl.

In another embodiment, in compounds of formula I, ring A-(R^(A)), isselected from the group consisting of

In another embodiment, in compounds of formula I, ring A-(R^(A))_(n) isselected from the group consisting of

In another embodiment, in compounds of formula I, ring A is anoptionally substituted ring selected from the group consisting ofazetidine, pyrrolidine, piperidine, homopiperidine,(1R,5S)-8-azabicyclo[3.2.1]octane, 3-oxa-9-azabicyclo[3.3.1]nonane,(1s,4s)-7-azabicyclo[2.2.1]heptane, (1R,4S)-5-azabicyclo[2.1.1]hexane,7-(trifluoromethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine andquinuclidine

In another embodiment, in compounds of formula I, A is selected from thegroup consisting of

In another embodiment, in compounds of formula I, R^(A) is selected fromthe group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₅ cycloalkyl,C₂₋₄ heterocycloalkyl, F, Cl, Br, I, —OH, —NH₂, —CN, —NO₂, C₁₋₄ alkoxy,—C(═O)—N(R^(A1))(R^(A2)) and —N(R^(A1))(R^(A2)).

In another embodiment, in compounds of formula I, wherein the group:

is selected from the group consisting of

In another embodiment, in compounds of formula I, ring A is selectedfrom the group consisting of

In another embodiment, in compounds of formula I, R^(A) is methyl,trifluoromethyl, difluoromethyl, monofluoromethyl, ethyl,pentafluoroethyl, cyclopropyl, —F, Cl, —OH, —NH₂ or —CN.

In another embodiment, in compounds of formula I, B is C; R³ is H, R² isF, Cl, Br, or I; and R⁵ is C₃₋₈ cycloalkyl, wherein said C₃₋₈ cycloalkylis further optionally substituted with from 1 to 3 R^(5a) substituentsselected from F, Cl, Br, I, —OH, ═O, C₃₋₆ cycloalkyl, —CN, C₁₋₄ alkyl,—C₁₋₄ alkyl-O—C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ alkoxy.

In another embodiment, in compounds of formula I, R⁵ is C₃₋₈ cycloalkyl.

In another embodiment, in compounds of formula I, the group:

is selected from the group consisting of

In another embodiment, in compounds of formula I, the group:

is selected from the group consisting of

In another embodiment, in compounds of formula I, the compound isselected from the group consisting of compounds set forth in Table 1.

TABLE 1 No Structure Name  1

tert-butyl 3-((2,5-difluoro-4-((methylsufonyl)carbamoyl)phenoxy)methyl)piperidine- 1-carboxylate  2

4-(2-cyclopropylethoxy)-2,5-difluoro-N- (methylsulfonyl)benzamide  3

2,5-difluoro-N-(methylsulfonyl)-4-(piperidin-3- ylmethoxy)benzamide  4

2,5-difluoro-N-(methylsulfonyl)-4-((tetrahydrofuran-2-yl)methoxy)benzamide  5

4-((adamantan-1-ylmethoxy)-2,5-difluoro-N- (methylsulfonyl)benzamide  6

4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N- (methylsulfonyl)benzamide 7

tert-butyl 4-(2-(2,5-difluoro-4-((methylsulfonyl)carbamoyl)phenoxy)ethyl)piperidine- 1-carboxylate  8

5-chloro-4-(((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide  9

4-(adamantan-2-yloxy)-5-chloro-2-fluoro-N- (methylsulfonyl)benzamide  10

5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3- yl)oxy)benzamide 11

4-(2-(adamantan-1-yl)ethoxy)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide  12

5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)benzamide  13

5-chloro-2-fluoro-N-(methylsulfonyl)-4-((exo-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)benzamide  14

5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3- yl)oxy)benzamide 15

5-chloro-4-(2-cyclopropylethoxy)-2-fluoro-N- (methylsulfonyl)benzamide 16

5-chloro-2-fluoro-4-((3-fluoroadamantan-1-yl)methoxy)-N-methylsulfonyl)benzamide  17

4-(((3s,5s,7s)-adamantan-1-ylamino)methyl)-3-chloro-N-(methylsulfonyl)benzamide  18

4-((-adamantan-1-ylmethyl)amino)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide  19

4-(adamantan-1-ylmethoxy)-3-chloro-N- (methylsulfonyl)benzamide  20

4-(2-(adamantan-1-yl)ethoxy)-3-chloro-N- (methylsulfonyl)benzamide  21

6-(adamantan-1-ylmethoxy)-5-chloro-N-methanesulfonylpyridine-3-carboxamide  22

5-chloro-2-fluoro-N-(methylsulfonyl)-4-(5,6,7,8-tetrahydronaphthalen-2-yloxy)benzamide  23

5-chloro-4-((-3,5-dimethyladamantan-1-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide  24

3-chloro-4-(((1r,3s,5R,7S)-3-hydroxyadamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamide  25

5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)benzamide  26

4-(adamantan-1-ylmethoxy)-5-chloro-N-(N,N-dimethylsulfamoyl)-2-fluorobenzamide  27

N1-((3s,5s,7s)-adamantan-1-yl)-2-chloro-5-fluoro-N4-(methylsulfonyl)terephthalamide  28

5-chloro-2-fluoro-4-((3-hydroxyadamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamide  29

5-chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethylcyclopropyl)methoxy)benzamide  30

5-chloro-4-(cyclohexylmethoxy)-2-fluoro-N- (methylsulfonyl)benzamide  31

4-(1-(adamantan-1-yl)ethoxy)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide  32

5-chloro-4-(2-cyclopentylethoxy)-2-fluoro-N- (methylsulfonyl)benzamide 33

4-(adamantan-2-yloxy)-5-chloro-N-(N,N-dimethylsulfamoyl)-2-fluorobenzamide  34

5-chloro-4-(((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methoxy)-N-(N,N-dimethylsulfamoyl)-2-fluorobenzamide  35

4-(((3s,5s,7s)-adamantan-1-yl(methyl)amino)methyl)-3-chloro-N-(methylsulfonyl)benzamide  36

5-chloro-4-(2-cyclohexylethoxy)-2-fluoro-N- (methylsulfonyl)benzamide 37

N1-((3s,5s,7s)-adamantan-1-yl)-2-chloro-5-fluoro-N1-methyl-N4-(methylsulfonyl)terephthalamide  38

5-chloro-2-fluoro-4-((3-methoxyadamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamide  39

5-chloro-2-fluoro-N-(methylsulfonyl)-4-((4-pentylbicyclo[2.2.2]octan-1-yl)methoxy)benzamide  40

5-chloro-4-(((1R,2s,3S,5s,7s)-5-chloroadamantan-2-yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide  41

5-chloro-4-(((1R,2r,3S,5s,7s)-5-chloroadamantan-2-yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide  42

5-chloro-4-(2-cycloheptylethoxy)-2-fluoro-N- (methylsulfonyl)benzamide 43

6-(1-adamantylmethoxy)-5-cyclopropyl-N-methylsulfonyl-pyridine-3-carboxamide  44

4-(2-adamantyloxymethyl)-5-cyclopropyl-2-fluoro-N-methylsulonyl-benzamide  45

4-(1-adamantylmethoxy)-5-ethyl-2-fluoro-N- methylsulfonyl-benzamide  46

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-ethyl-2-fluoro-benzamide  47

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(3-hydroxyazetidin-1-yl)sulfonyl-benzamide  48

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(2-hydroxyethylsulfonyl)benzamide  49

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(2-methoxyethylsulfonyl)benzamide  50

5-chloro-2-fluoro-N-methylsulfonyl-4-(spiro[2.5]octan-6-ylmethoxy)benzamide  51

4-(1-adamantylmethoxy)-3-cyclobutyl-N- methylsulfonyl-benzamide  52

4-(2-adamantyloxymethyl)-5-chloro-2-fluoro-N- methylsulfonyl-benzamide 53

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-3-(trifluoromethyl)benzamide  54

5-chloro-4-[[(1R,2R,5R)-6,6-dimethylnorpinan-2-yl]methoxy]-2-fluoro-N-methylsulfonyl-benzamide  55

4-(2-adamantylmethoxy)-3-cyclopropyl-N- methylsulfonyl-benzamide  56

4-(1-adamantylmethoxy)-5-chloro-2-methoxy-N- methylsulfonyl-benzamide 57

N-(azetidin-1-ylsulfonyl)-5-chloro-4-[(2,2-dimethylchroman-6-yl)oxymethyl]-2-fluoro-benzamide  58

5-chloro-4-[(3,3-dimethyltetralin-6-yl)oxymethyl]-2-fluoro-N-(methylsulfamoyl)benzamide  59

5-chloro-4-[(2,2-dimethyl)tetralin-6-yl)oxymethyl]-2-fluoro-N-(methylsulfamoyl)benzamide  60

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-methylsulfonyl-benzamide  61

4-(1-adamantylmethoxy)-3-bromo-N-methylsulfonyl- benzamide  62

4-(1-adamantylmethoxy)-N-methylsulfonyl-3- (trifluoromethyl)benzamide 63

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(methylsulamoyl)benzamide  64

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-benzamide  65

5-chloro-4-[(2,2-dimethylchroman-6-yl)oxymethyl]-2-fluoro-N-(methylsulfamoyl)benzamide  66

5-chloro-4-[(2,2-dimethylchroman-7-yl)oxymethyl]-2-fluoro-N-(methylsulfamoyl)benzamide  67

4-(1-adamantylmethoxy)-5-chloro-2-fluoro-N-(2-hydroxyethylsulfonyl)benzamide  68

4-(1-adamantylmethoxy)-2,5-dichloro-N- methylsulfonyl-benzamide  69

4-(1-adamantylmethoxy)-5-chloro-2-fluoro-N- (methylsulfamoyl)benzamide 70

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-benzamide  71

4-(1-adamantylmethoxy)-5-chloro-2-fluoro-N-(1-methylimidazol-4-yl)sulfonyl-benzamide  72

4-(1-adamantylmethoxy)-5-chloro-2-fluoro-N-(2-methoxyethylsulfonyl)benzamide  73

4-(1-adamantylmethoxy)-5-chloro-2-fluoro-N-(1H-imidazol-4-ylsulfonyl)benzamide  74

4-(1-adamantylmethoxy)-5-chloro-2-fluoro-N- morpholinsulfonyl-benzamide 75

5-chloro-2-fluoro-N-methylsulfonyl-4-[[3-(5-methyltetrazol-2-yl)-1-adamantyl]methoxy]benzamide  76

5-chloro-4-[(2,2-dimethylchroman-7-yl)oxymethyl]-N-(dimethylsulfamoyl)-2-fluoro-benzamide  77

5-chloro-N-(dimethylsulfamoyl)-4-[(2,2-dimethyltetralin-6-yl)oxymethyl]-2-fluoro-benzamide  78

5-chloro-N-(dimethylsulfamoyl)-2-fluoro-4-[(1-pentyl-4-bicyclo[2.2.2]octanyl)methxoy]benzamide  79

5-chloro-4-[(3-chloro-1-adamantyl)methoxy]-N-(dimethylsulfamoyl)-2-fluoro-benzamide  80

5-chloro-N-(dimethylsulfamoyl)-2-fluoro-4-[(1-fluorocyclohexyl)methoxy]benzamide  81

5-chloro-2-fluoro-N-methylsulfonyl-4-[[1-(trifluoromethyl)cyclobutyl]methoxy]benzamide  82

5-chloro-N-(dimethylsulfamoyl)-2-fluoro-4-[[1-(trifluoromethyl)cyclobutyl]methoxy]benzamide  83

5-chloro-N-(dimethylsulfamoyl)-4-[(3,3-dimethyltetralin-6-yl)oxymethyl]-2-fluoro-benzamide  84

4-(1-adamantylmethoxy)-3-cyclopropyl-N- (dimethylsulfamoyl)benzamide  85

4-(1-adamantyloxymethyl)-5-chloro-2-fluoro-N- methylsulfonyl-benzamide 86

4-(1-adamantylmethoxy)-3-cyclopropyl-N- methylsulfonyl-benzamide  87

5-chloro-N-(dimethylsulfamoyl)-2-fluoro-4-(spiro[3.5]nonan-7-ylmethoxy)benzamide  88

5-chloro-N-(dimethylsulfamoyl)-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide  89

5-chloro-N-(dimethylsulfamoyl)-2-fluoro-4-[(3-fluoro-1-adamantyl)methoxy]benzamide  90

5-chloro-2-fluoro-N-methylsulfonyl-4-[(2,2,3,3-tetramethylcyclopropyl)methoxy]benzamide  91

5-chloro-2-fluoro-N-methylsulfonyl-4-[[(1S,5R)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3- yl]methoxy]benzamide 92

5-chloro-4-[(4,4-difluoro-1-adamantyl)methoxy]-N-(dimethylsulfamoyl)-2-fluoro-benzamide  93

5-chloro-2-fluoro-N-methylsulfonyl-4-[[4-(trifluoromethyl)cyclohexyl]methoxy]benzamide  94

5-chloro-4-[[(1S,2S,5S)-6,6-dimethylnorpinan-2-yl]methoxy]-2-fluoro-N-sulfamoyl-benzamide  95

5-chloro-2-fluoro-N-methylsulfonyl-4-(spiro[3.5]nonan-7-ylmethoxy)benzamide  96

5-chloro-4-[[(1S,2R,5S)-6,6-dimethylnorpinan-2-yl]methoxy]-N-(dimethylsulfamoyl)-2-fluoro- benzamide  97

4-(2-adamantylmethoxy)-5-chloro-N-(dimethylsulfamoyl)-2-fluoro-benzamide  98

5-chloro-N-(dimethylsulfamoyl)-2-fluoro-4-(norbornan-2-ylmethoxy)benzamide  99

5-chloro-4-[(4,4-difluorocyclohexyl)methoxy]-2-fluoro-N-methylsulfonyl-benzamide 100

5-chloro-4-(cycloheptylmethoxy)-N-(dimethylsulfamoyl)-2-fluoro-benzamide 101

5-chloro-4-(cyclohexylmethoxy)-N- (dimethylsulfamoyl)-2-fluoro-benzamide102

5-chloro-4-(cyclopentylmethoxy)-N-(dimethylsulfamoyl)-2-fluoro-benzamide 103

5-chloro-2-fluoro-N-methylsulfonyl-4-[[1-(trifluoromethyl)cyclopropyl]methoxy]benzamide 104

5-chloro-4-[(3-chloro-1-adamantyl)methoxy]-2-fluoro-N-methylsulfonyl-benzamide 105

5-chloro-4-(cyclopentylmethoxy)-2-fluoro-N- methylsulfonyl-benzamide 106

5-chloro-2-fluoro-N-methylsulfonyl-4-[[4-(trifluoromethyl)cyclohexyl]methoxy]benzamide 107

5-chloro-4-[[(1S,2R,5S)-6,6-dimethylnorpinan-2-yl]methoxy]-2-fluoro-N-methylsulfonyl-benzamide 108

4-(1-adamantylmethoxy)-3-(2-methoxy-3-pyridyl)-N-methylsulfonyl-benzamide 109

4-(2-adamantylmethoxy)-5-chloro-2-fluoro-N- methylsulfonyl-benzamide 110

5-chloro-2-fluoro-N-methylsulfonyl-4-(tetralin-6- yloxymethyl)benzamide111

3-chloro-N-methylsulfonyl-4-[(2,2,3,3-tetramethylcyclopropyl)methoxy]benzamide 112

5-chloro-4-[[(1S,5R)-6,6-dimethyl-4-bicyclo[3.1.1]hept-3-enyl]methoxy]-2-fluoro-N-methylsulfonyl-benzamide 113

5-chloro-2-fluoro-N-methylsulfonyl-4-(norbornan-2- ylmethoxy)benzamide114

5-chloro-4-(cycloheptylmethoxy)-2-fluoro-N- methylsulfonyl-benzamide 115

5-chloro-2-fluoro-N-methylsulfonyl-4-[(1-pentyl-4-bicyclo[2.2.2]octanyl)methoxy]benzamide 116

5-chloro-2-fluoro-N-methylsulfonyl-4-[(1S,2R,4R)-norbornan-2-yl]oxy-benzamide 117

5-chloro-2-fluoro-N-methylsulfonyl-4-[(1R,2R,4S)-1,3,3-trimethylnorbornan-2-yl]oxy-benzamide 118

5-chloro-2-fluoro-4-[(1S,2R,5S)-2-isopropyl-5-methyl-cyclohexoxy]-N-methylsulfonyl-benzamide 119

5-chloro-2-fluoro-N-methylsulfonyl-4-norbornan-2- yloxy-benzamide 120

121

5-chloro-2-fluoro-4-(4-isopropylcyclohexoxy)-N- methylsulfonyl-benzamide122

5-chloro-4-(3,3-dimethylcyclohexoxy)-2-fluoro-N-methylsulfonyl-benzamide 123

5-chloro-4-(4,4-dimethylcyclohexoxy)-2-fluoro-N-methylsulfonyl-benzamide 124

5-chloro-4-(cyclohexoxy)-2-fluoro-N-methylsulfonyl- benzamide 125

5-chloro-N-(dimethylsulfamoyl)-2-fluoro-4-[(1S,2R,4S)-1,7,7-trimethylnorbornan-2-yl]oxy- benzamide 126

5-chloro-2-fluoro-N-methylsulfonyl-4-[4-(trifluoromethyl)cyclohexoxy]benzamide 127

5-chloro-4-(2-cyclohexylethoxy)-N-(dimethylsulfamoyl)-2-fluoro-benzamide 128

5-chloro-2-fluoro-N-methylsulfonyl-4-[4-(trifluoromethyl)cyclohexoxy]benzamide 129

5-chloro-4-[(5-chloro-2-adamantyl)oxy]-N-(dimethylsulfamoyl)-2-fluoro-benzamide 130

5-chloro-4-(2-cyclopentylethoxy)-N-(dimethylsulfamoyl)-2-fluoro-benzamide 131

5-chloro-N-(dimethylsufamoyl)-2-fluoro-4-(4-isopropylcyclohexoxy)benzamide 132

5-chloro-4-[(5-chloro-2-adamantyl)oxy]-N-(dimethylsulfamoyl)-2-fluoro-benzamide 133

5-chloro-2-fluoro-N-methylsulfonyl-4-spiro[4.5]decan- 8-yloxy-benzamide134

5-chloro-2-fluoro-N-methylsulfonyl-4-spiro[5.5]undecan-3-yloxy-benzamide 135

136

5-chloro-4-(2-cycloheptylethoxy)-N-(dimethylsulfamoyl)-2-fluoro-benzamide 137

5-chloro-4-(3-cyclohexylpropoxy)-N-(dimethylsulfamoyl)-2-fluoro-benzamide 138

5-chloro-N-(dimethylsulfamoyl)-2-fluoro-4-[4-(trifluoromethyl)cyclohexoxy]benzamide 139

5-chloro-N-(dimethylsulfamoyl)-2-fluoro-4-spiro[5.5]undecan-3-yloxy-benzamide 140

5-chloro-4-(2-cyclobutylethoxy)-N-(dimethylsulfamoyl)-2-fluoro-benzamide 141

5-chloro-N-(dimethylsulfamoyl)-2-fluoro-4-spiro[4.5]decan-8-yloxy-benzamide 142

5-chloro-N-(dimethylsulfamoyl)-2-fluoro-4-[4-(trifluoromethyl)cyclohexoxy]benzamide 143

5-chloro-4-(3-cyclopentylpropoxy)-N-(dimethylsulfamoyl)-2-fluoro-benzamide 144

4-[2-(1-adamantyl)ethoxy]-5-chloro-N-(dimethylsulfamoyl)-2-fluoro-benzamide 145

146

4-(1-adamantylmethoxy)-5-chloro-N-cyclopropylsulfonyl-2-fluoro-benzamide 147

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-[(3S)-3-hydroxypyrrolidin-1-yl]sulfonyl-benzamide 148

4-(1-adamantylmethoxy)-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-benzamide 149

4-(1-adamantylmethoxy)-5-chloro-2-fluoro-N-[(3S)-3-hydroxypyrrolidin-1-yl]sulfonyl-benzamide 150

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(3-fluoroazetidin-1-yl)sulfonyl-benzamide 151

4-(1-adamantylmethoxy)-5-chloro-2-fluoro-N-(3-fluoroazetidin-1-yl)sulfonyl-benzamide 152

5-chloro-4-[(4,4-difluoro-1-adamantyl)methoxy]-2-fluoro-N-methylsulfonyl-benzamide 153

5-cyclopropyl-4-[(4,4-difluoro-1-adamantyl)methoxy]-2-fluoro-N-methylsulfonyl-benzamide 154

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-pyrrolidin-1-ylsulfonyl-benzamide 155

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-morpholinosulfonyl-benzamide 156

5-cyclopropyl-2-fluoro-4-[(3-fluoro-1-adamantyl)methoxy]-N-methylsulfonyl-benzamide 157

5-cyclopropyl-2-fluoro-4-[(3-methoxy-1-adamantyl)methoxy]-N-methylsulfonyl-benzamide 158

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-(spiro[2.5]octan-6-ylmethoxy)benzamide 159

4-(1-adamantylmethoxy)-5-cyclopropyl-N-(3,3-difluoroazetidin-1-yl)sulfonyl-2-fluoro-benzamide 160

2-fluoro-4-[(3-fluoro-1-adamantyl)methoxy]-N- methylsulfonyl-benzamide161

4-(1-adamantylmethoxy)-2-fluoro-5-methyl-N- methylsulfonyl-benzamide 162

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-methyl-benzamide 163

4-(1-adamantylmethoxy)-5-cyclopropyl-N- ethylsulfonyl-2-fluoro-benzamide164

4-(1-adamantylmethoxy)-N-tert-butylsulfonyl-5-cyclopropyl-2-fluoro-benzamide 165

2-fluoro-N-methylsulfonyl-4-(spiro[2.5]octan-6- ylmethoxy)benzamide 166

5-cyclopropyl-4-[(4,4-difluorocyclohexyl)methoxy]-2-fluoro-N-methylsulfonyl-benzamide 167

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(2-methoxyethylsulfamoyl)benzamide 168

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(3-hydroxypropylsulfamoyl)benzamide 169

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(3-methoxyazetidin-1-yl)sulfonyl-benzamide 170

Azetidine-1-sulfonic acid 5-cyclopropyl-4-(4,4-difluoro-adamantan-1-ylmethoxy)-2-fluoro-benzoylamide 171

Cyclopropanesulfonic acid 4-(bicyclo[4.1.0]hept-1-ylmethoxy)-5-cyclopropyl-2-fluoro-benzoylamide 172

trans-2-fluoro-4-[(5-fluoro-2-adamantyl)oxy]-5-methyl-N-methylsulfonyl-benzamide 173

cis-5-chloro-2-fluoro-4-[(5-fluoro-2-adamantyl)oxy]-N-methylsulfonyl-benzamide 174

6-(1-adamantylmethoxy)-5-cyclopropyl-N-(2-hydroxyethylsulfonyl)pyridine-3-carboxamide 175

4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N- methylsulfonyl-benzamide176

5-chloro-2-fluoro-4-[(2-fluoro-2-adamantyl)methoxy]-N-methylsulfonyl-benzamide 177

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(3-hydroxyoxetan-3-yl)benzamide 178

6-(1-adamantylmethoxy)-5-cyclopropyl-N-(methylsulfamoyl)pyridine-3-carboxamide 179

4-(2-adamantyl)-3-chloro-N- (methylsulfamoyl)benzamide 180

4-(2-adamantyl)-3-chloro-N-methylsulfonyl-benzamide 181

5-cyclopropyl-2-fluoro-4-[(2-fluoro-2-adamantyl)methoxy]-N-methylsulfonyl-benzamide 182

5-chloro-2-fluoro-N-methylsulfonyl-4-[(3,5,7-trifluoro-1-adamantyl)methoxy]benzamide 183

5-chloro-N-methylsulfonyl-6-[(3,5,7-trifluoro-1-adamantyl)methoxy]pyridine-3-carboxamide 184

4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfomoyl)benzamide 185

N-(azetidin-1-ylsulfonyl)-4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-benzamide 186

4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-(2-methoxyethylsulfonyl)benzamide 187

5-chloro-4-[(2-cyano-2-adamantyl)methoxy]-2-fluoro-N-(2-methoxyethylsulfonyl)benzamide 188

5-chloro-4-[(2-cyano-2-adamantyl)methoxy]-2-fluoro-N-(methylsulfamoyl)benzamide 189

5-chloro-4-[(2-cyano-2-adamantyl)methoxy]-2-fluoro-N-methylsulfonyl-benzamide 190

4-(2-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-methylsulfonyl-benzamide 191

4-(2-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-benzamide 192

4-(2-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(2-methoxyethylsulfonyl)benzamide 193

4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-(2-hydroxyethylsulfonyl)benzamide 194

4-[2-adamantyl(hydroxy)methyl]-3-chloro-N- methylsulfonyl-benzamide 195

4-(1-adamantylmethoxy)-2-fluoro-5-iodo-N- methylsulfonyl-benzamide 196

4-(1-adamantylmethoxy)-5-cyclopropyl-N-(2-ethoxyethylsulfonyl)-2-fluoro-benzamide 197

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(3-methoxypropylsulfonyl)benzamide 198

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-[(3,5,7-trifluoro-1-adamantyl)methoxy]benzamide 199

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-tetrahydropyran-4-ylsulfonyl-benzamide 200

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-tetrahydrofuran-3-ylsulfonyl-benzamide 201

cis-5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-[[4-(trifluoromethyl)cyclohexyl]methoxy]benzamide 202

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(2-isopropoxyethylsulfonyl)benzamide 203

4-(1-adamantylmethoxy)-3,5-dichloro-N- methylsulfonyl-benzamide 204

4-(1-adamantylmethoxy)-N-(3-cyanoazetidin-1-yl)sulfonyl-5-cyclopropyl-2-fluoro-benzamide 205

4-[(2-cyano-2-adamantyl)methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonyl-benzamide 206

4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-[(3S)-3-hydroxypyrrolidin-1-yl]sulfonyl-benzamide 207

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(1-hydroxyethyl)benzamide 208

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-[[1-(trifluoromethyl)cyclohexyl]methoxy]benzamide 209

trans-4-[(5-chloro-2-adamantyl)oxy]-5-cyclopropyl-2-fluoro-N-morpholinosulfonyl-benzamide 210

4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-(3-fluoroazetidin-1-yl)sulfonyl-benzamide 211

4-(1-adamantylmethoxy)-N-cyclobutylsulfonyl-5-cyclopropyl-2-fluoro-benzamide 212

4-[[(1R,5S)-3-bicyclo[3.1.0]hexanyl]oxy]-5-chloro-2-fluoro-N-(methylsulfamoyl)benzamide 213

4-[[(1R,5S)-3-bicyclo[3.1.0]hexanyl]oxy]-5-chloro-2-fluoro-N-methylsulfonyl-benzamide 214

4-[[(1R,5S)-3-bicyclo[3.1.0]hexanyl]oxy]-5-chloro-2-fluoro-N-(3-fluoroazetidin-1-yl)sulfonyl-benzamide 215

4-(1-adamantylmethoxy)-2-fluoro-N-(2- hydroxypropylsulfonyl)benzamide216

4-[(2-cyano-2-adamantyl)methoxy]-5-cyclopropyl-2-fluoro-N-(methylsulfamoyl)benzamide 217

5-cyclopropyl-N-cyclopropylsulfonyl-4-[(4,4-difluorocyclohexyl)methoxy]-2-fluoro-benzamide 218

4-(1-adamantyloxymethyl)-N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-benzamide 219

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(3,5,7-trifluoro-1-adamantyl)methoxy]benzamide 220

5-cyclopropyl-2-fluoro-N-(3-fluoroazetidin-1- yl)sulfonyl-4-[[1-(trifluoromethyl)cyclohexyl]methoxy]benzamide 221

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[[1-(trifluoromethyl)cyclohexyl]methoxy]benzamide 222

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-iodo-benzamide 223

N-(azetidin-1-ylsulfonyl)-5-chloro-4-[(2-cyano-2-adamantyl)methoxy]-2-fluoro-benzamide 224

N-(azetidin-1-ylsulfonyl)-4-[(2-cyano-2-adamantyl)methoxy]-5-cyclopropyl-2-fluoro-benzamide 225

5-cyclopropyl-4-[(4,4-difluorocyclohexyl)methoxy]-2-fluoro-N-(2-methoxyethylsulfonyl)benzamide 226

5-cyclopropyl-4-[(4,4-difluorocyclohexyl)methoxy]-2-fluoro-N-(3-fluoroazetidin-1-yl)sulfonyl-benzamide 227

5-acetyl-4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-benzamide 228

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(1-hydroxy-1-methyl-ethyl)benzamide 229

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(2-oxa-7-azaspiro[3.5]nonan-7-ylsulfonyl)benzamide 230

5-cyclopropyl-2-fluoro-N-(2-methoxyethylsulfonyl)-4-[[1-(trifluoromethyl)cyclohexyl]methoxy]benzamide 231

N-(azetidin-1-ylsulfonyl)-4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluoro-benzamide 232

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[[3-(hydroxymethyl)-1-adamantyl]methoxy]benzamide 233

5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-[(3,5,7-trifluoro-1-adamantyl)methoxy]benzamide 234

N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-[[1-(trifluoromethyl)cyclopentyl]methoxy]benzamide 235

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(1-methylcyclohexyl)methoxy]benzamide 236

[3-[[4-(azetidin-1-ylsulfonylcarbamoyl)-2-cyclopropyl-5-fluoro-phenoxy]methyl]-1-adamantyl] 2,2,2- trifluoroacetate 237

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(2-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)benzamide 238

5-cyclopropyl-2-fluoro-N-(methylsulfamoyl)-4-[[1-(trifluoromethyl)cyclohexyl]methoxy]benzamide 239

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(3,3-dimethylcyclohexyl)methoxy]-2-fluoro-benzamide 240

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[[3-(fluoromethyl)-1-adamantyl]methoxy]benzamide 241

5-cyclopropyl-4-[(4,4-difluorocyclohexyl)methoxy]-2-fluoro-N-(methylsulfamoyl)benzamide 242

4-(cyclopentylmethoxy)-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-benzamide 243

4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluoro-N-(2-methoxyethylsulfonyl)benzamide 244

4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluoro-N-(3-methoxyazetidin-1-yl)sulfonyl-benzamide 245

5-cyclopropyl-N-cyclopropylsulfonyl-4-[(4,4-difluoro-1-methyl-cyclohexyl)methoxy]-2-fluoro-benzamide 246

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(4,4-difluoro-1-methyl-cyclohexyl)methoxy]-2-fluoro- benzamide 247

5-cyclopropyl-4-[(4,4-difluoro-1-methyl-cyclohexyl)methoxy]-2-fluoro-N-methylsulfonyl- benzamide 248

5-cyclopropyl-4-[(4,4-difluoro-1-adamantyl)methoxy]-2-fluoro-N-(3-fluoroazetidin-1-yl)sulfonyl-benzamide 249

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[[1-(trifluoromethyl)cyclopentyl]methoxy]benzamide 250

5-cyclopropyl-4-[(4,4-difluoro-1-adamantyl)methoxy]-2-fluoro-N-(2-methoxyethylsulfonyl)benzamide 251

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(4,4-difluoro-1-adamantyl)methoxy]-2-fluoro-benzamide 252

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-tetrahydrofuran-3-ylsulfonyl-benzamide 253

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(1-fluoro-1-methyl-ethyl)benzamide 254

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-tetrahydrofuran-3-ylsulfonyl-benzamide 255

5-cyclopropyl-4-[(4,4-difluoro-1-methyl- cyclohexyl)methoxy]-2-fluoro-N-(methylsulfamoyl)benzamide 256

5-cyclopropyl-4-[(4,4-difluoro-1-methyl-cyclohexyl)methoxy]-2-fluoro-N-(2- methoxyethylsulfonyl)benzamide 257

4-(3-bicyclo[3.1.0]hexanylmethoxy)-5-cyclopropyl-2-fluoro-N-methylsulfonyl-benzamide 258

4-(3-bicyclo[3.1.0]hexanylmethoxy)-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-benzamide 259

4-[[(1R,5S)-6-bicyclo[3.1.0]hexanyl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonyl-benzamide 260

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(3-hydroxy-1-adamantyl)methoxy]benzamide 261

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(1-oxa-6-azaspiro[3.3.]heptan-6-ylsulfonyl)benzamide 262

5-cyclopropyl-N-cyclopropylsulfonyl-4-[(4,4-difluoro-1-adamantyl)methoxy]-2-fluoro-benzamide 263

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(1-hydroxyethyl)benzamide 264

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(1-hydroxyethyl)benzamide 265

N-(azetidin-1-ylsulfonyl)-4-(3-bicyclo[3.1.0]hexanylmethoxy)-5-chloro-2-fluoro- benzamide 266

4-(3-bicyclo[3.1.0]hexanylmethoxy)-5-chloro-N-cyclopropylsulfonyl-2-fluoro-benzamide 267

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-[[1-(trifluoromethyl)cyclopropyl]methoxy]benzamide 268

5-chloro-2-fluoro-N-methylsulfonyl-4- [(1,2,2,3,3,4,4,5,5,6,6-undecadeuteriocyclohexyl)methoxy]benzamide 269

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-(norcaran-1-ylmethoxy)benzamide 270

5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-(norcaran-1-ylmethoxy)benzamide 271

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(4-fluoronorcaran-1-yl)methoxy]benzamide 272

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-cyclobutyl-2-fluoro-benzamide 273

4-(1-adamantylmethoxy)-5-cyclobutyl-N-cyclopropylsulfonyl-2-fluoro-benzamide 274

4-(1-adamantylmethoxy)-(azetidin-1-ylsulfonyl)-5-[cyclopropyl(hydroxy)methyl]-2-fluoro-benzamide 275

N-(azetidin-1-ylsulfonyl)-3-chloro-4-[3-(2-methylallyloxy)cyclohexyl]benzamide 276

N-(azetidin-1-ylsulfonyl)-4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yloxy)-5-chloro-2- fluorobenzamide 277

278

N-(azetidin-1-ylsulfonyl)-4-(4-chlorocyclohex-3-enyloxy)-5-cyclopropyl-2-fluorobenzamide 279

280

6-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-pyridine-3-carboxamide 281

6-(1-adamantylmethoxy)-5-cyclopropyl-N-(2-methoxyethylsulfonyl)pyridine-3-carboxamide 282

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(1-fluorocyclohexyl)methoxy]benzamide 283

trans-N-(azetidin-1-ylsulfonyl)-4-[(5-chloro-2-adamantyl)oxy]-5-cyclopropyl-2-fluoro-benzamide 284

5-cyclopropyl-2-fluoro-N-(2-methoxyethylsulfonyl)-4-(norcaran-1-ylmethoxy)benzamide 285

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-[(4-hydroxy-1-piperidyl)sulfonyl]benzamide 286

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide 287

2-fluoro-N-methylsulfonyl-4-[[4-(trifluoromethyl)cyclohexyl]methoxy]benzamide 288

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-[[4-(trifluoromethyl)cyclohexyl]methoxy]benzamide 289

N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide 290

5-cyclopropyl-4-[(4,4-difluoro-1-methyl-cyclohexyl)methoxy]-2-fluoro-N-(3-fluoroazetidin-1-yl)sulfonyl-benzamide 291

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-[4-(trifluoromethyl)cyclohexoxy]benzamide 292

5-chloro-4-(4-chlorocyclohex-3-en-1-yl)oxy-N-cyclopropylsulfonyl-2-fluoro-benzamide 293

5-chloro-N-cyclopropylsulfonyl-4-(4,4-dichlorocyclohexoxy)-2-fluoro-benzamide 294

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(4-ethylcyclohex-3-en-1-yl)methoxy]-2-fluoro-benzamide 295

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4- [(1,2,2,3,3,4,4,5,5,6,6-undecadeuteriocyclohexyl)methoxy]benzamide 296

N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4- [(1,2,2,3,3,4,4,5,5,6,6-undecadeuteriocyclohexyl)methoxy]benzamide 297

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(1,2,2,3,3,4,4,5,5,6,6- undecadeuteriocyclohexyl)methoxy]benzamide 298

5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-[(1S,2R,4R)-norbornan-2-yl]oxy-benzamide 299

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(1S,2R,4R)-norbornan-2-yl]oxy-benzamide 300

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-[(1S,2R,4R)-norbornan-2-yl]oxy-benzamide 301

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-[(3R)-3-methoxypyrrolidin-1-yl]sulfonyl-benzamide 302

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[2-(4,4-difluorocyclohexyl)ethoxy]-2-fluoro-benzamide 303

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(1S,2S,4R)-norbornan-2-yl]oxy-benzamide 304

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-[(1S,2S,4R)-norbornan-2-yl]oxy-benzamide 305

5-chloro-4-[(4,4-difluoro-1-methyl-cyclohexoxy)methyl]-2-fluoro-N-methylsulfonyl- benzamide 306

4-(1-adamantylmethoxy)-3-chloro-2,5-difluoro-N- methylsulfonyl-benzamide307

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-3-chloro-2,5-difluoro-benzamide 308

5-cyclopropyl-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)-N-(methylsulfonyl)benzamide 309

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(4,4-dimethylcyclohexyl)methoxy]-2-fluoro-benzamide 310

5-cyclopropyl-4-[(7,7-difluoronorcaran-1-yl)methoxy]-2-fluoro-N-methylsulfonyl-benzamide 311

5-cyclopropyl-4-[(7,7-difluoronorcaran-1-yl)methoxy]-2-fluoro-N-(2-methoxyethylsulfonyl)benzamide 312

5-cyclopropyl-N-cyclopropylsulfonyl-4-[(7,7-difluoronorcaran-1-yl)methoxy]-2-fluoro-benzamide 313

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(7,7-difluoronorcaran-1-yl)methoxy]-2-fluoro-benzamide 314

N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(spiro[3.5]nonan-7-ylmethoxy)benzamide 315

5-chloro-N-cyclopropylsulfonyl-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide 316

N-(azetidin-1-ylsulfonyl)-5-chloro-4-[(6,6-difluoro-3-bicyclo[3.1.0]hexanyl)methoxy]-2-fluoro-benzamide 317

5-chloro-N-cyclopropylsulfonyl-4-[(6,6-difluoro-3-bicyclo[3.1.0]hexanyl)methoxy]-2-fluoro-benzamide 318

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-vinyl-benzamide 319

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-[(3S)-3-methoxypyrrolidin-1-yl]sulfonyl-benzamide 320

4-(1-adamantyloxymethyl)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-benzamide 321

N-(azetidin-1-ylsulfonyl)-5-chloro-4-[(6,6-difluoro-3-bicyclo[3.1.0]hexanyl)methoxy]-2-fluoro-benzamide 322

5-chloro-N-cyclopropylsulfonyl-4-[(6,6-difluoro-3-bicyclo[3.1.0]hexanyl)methoxy]-2-fluoro-benzamide 323

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-chloro-2,3-difluoro-benzamide 324

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-3-chloro-5-fluoro-benzamide 325

4-(1-adamantylmethoxy)-3-chloro-5-fluoro-N- methylsulfonyl-benzamide 326

4-(1-adamantylmethoxy)-5-chloro-2,3-difluoro-N- methylsulfonyl-benzamide327

5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-[[1-(trifluoromethyl)cyclobutyl]methoxy]benzamide 328

5-chloro-N-cyclopropylsulfonyl-2-fluoro-4-[[1-(trifluoromethyl)cyclobutyl]methoxy]benzamide 329

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[[1-(trifluoromethyl)cyclobutyl]methoxy]benzamide 330

N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-[[1-(trifluoromethyl)cyclobutyl]methoxy]benzamide 331

N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-[(4-fluoro-4-methyl-cyclohexyl)methoxy]benzamide 332

4-(2-adamantyloxy)-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-benzamide 333

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzamide 334

5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzamide 335

4-(2-adamantyloxy)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-benzamide 336

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-(4,4-difluorocyclohexoxy)-2-fluoro-benzamide 337

5-cyclopropyl-N-cyclopropylsulfonyl-4-(4,4-difluorocyclohexoxy)-2-fluoro-benzamide 338

N-(azetidin-1-ylsulfonyl)-5-chloro-4-(4,4-difluorocyclohexoxy)-2-fluoro-benzamide 339

5-chloro-N-cyclopropylsulfonyl-4-(4,4-difluorocyclohexoxy)-2-fluoro-benzamide 340

N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-[(4-fluoro-4-methyl-cyclohexyl)methoxy]benzamide 341

5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide 342

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-spiro[2.5]octan-6-yloxy-benzamide 343

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-spiro[2.5]octan-6-yloxy-benzamide 344

5-cyclopropyl-4-[(7,7-difluoronorcaran-3-yl)methoxy]-2-fluoro-N-methylsulfonyl-benzamide 345

5-cyclopropyl-N-cyclopropylsulfonyl-4-[(7,7-difluoronorcaran-3-yl)methoxy]-2-fluoro-benzamide 346

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(7,7-difluoronorcaran-3-yl)methoxy]-2-fluoro-benzamide 347

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-2-ylmethoxy)benzamide 348

4-(2-adamantyloxy)-5-cyclopropyl-2-fluoro-N- methylsulfonyl-benzamide349

5-cyclopropyl-2-fluoro-N-(3-fluoroazetidin-1-yl)sulfonyl-4-[(1-methylcyclohexyl)methoxy]benzamide 350

5-chloro-2-fluoro-4-[(5-methoxy-2-adamantyl)oxy]-N-methylsulfonyl-benzamide 351

cis-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide 352

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-(4,4-dichlorocyclohexoxy)-2-fluoro-benzamide 353

trans-4-(1-adamantylmethoxy)-2-fluoro-5-[2-(methoxymethyl)cyclopropyl]-N-methylsulfonyl- benzamide 354

N-(azetidin-1-ylsulfonyl)-4-[(1-cyanocyclohexyl)methoxy]-5-cyclopropyl-2-fluoro- benzamide 355

4-[(1-cyanocyclohexyl)methoxy]-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-benzamide 356

4-[(1-cyanocyclohexyl)methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonyl-benzamide 357

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-(3,3-dimethylcyclohexoxy)-2-fluoro-benzamide 358

5-cyclopropyl-4-(3,3-dimethylcyclohexoxy)-2-fluoro-N-methylsulfonyl-benzamide 359

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-spiro[5.5]undecan-3-yloxy-benzamide 360

5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-spiro[5.5]undecan-3-yloxy-benzamide 361

5-cyclopropyl-N-cyclopropylsulfonyl-4-(3,3-dimethylcyclohexoxy)-2-fluoro-benzamide 362

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-spiro[5.5]undecan-3-yloxy-benzamide 363

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(4-fluoro-4-methyl-cyclohexyl)methoxy]benzamide 364

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-(spiro[3.5]nonan-7-ylmethoxy)benzamide 365

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((cis-5-fluoroadamantan-2-yl)oxy)benzamide 366

cis-N-(azetidin-1-ylsulfonyl)-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzamide 367

5-chloro-4-(cyclohex-3-en-1-ylmethoxy)-2-fluoro-N-methylsulfonyl-benzamide 368

5-chloro-4-[(3,3-difluorocyclohexyl)methoxy]-2-fluoro-N-methylsulfonyl-benzamide 369

5-chloro-4-(cyclohexoxymethyl)-2-fluoro-N- methylsulfonyl-benzamide 370

5-chloro-4-(cyclohexoxymethyl)-N- cyclopropylsulfonyl-2-fluoro-benzamide371

N-(azetidin-1-ylsulfonyl)-5-chloro-4-(cyclohexoxymethyl)-2-fluoro-benzamide 372

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(2-methylcyclohexyl)methoxy]benzamide 373

5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-[(2-methylcyclohexyl)methoxy]benzamide 374

N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((cis-5-methoxyadamantan-2-yl)oxy)benzamide 375

cis-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide 376

N-(azetidin-1-ylsulfonyl)-4-[(4-chlorocyclohex-3-en-1-yl)methoxy]-5-cyclopropyl-2-fluoro-benzamide 377

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(4,4-dichlorocyclohexyl)methoxy]2-fluoro-benzamide 378

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-(2,2-difluorocyclopropyl)-2-fluoro-benzamide 379

4-(1-adamantylmethoxy)-N-cyclopropylsulfonyl-5-(2,2-difluorocyclopropyl)-2-fluoro-benzamide 380

4-(1-adamantylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluoro-N-methylsulfonyl-benzamide 381

4-butoxy-5-cyclopropyl-N-cyclopropylsulfonyl-2- fluoro-benzamide 382

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(4-fluoro-4-methyl-cyclohexyl)methoxy]benzamide 383

N-(azetidin-1-ylsulfonyl)-4-[(1-benzhydrylazetidin-3-yl)methoxy]-5-cyclopropyl-2-fluoro-benzamide 384

4-[(1-benzhydrylazetidin-3-yl)methoxy]-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-benzamide 385

4-[(1-benzhydrylazetidin-3-yl)methoxy]-5-cyclopropyl-2-fluoro-N-(methylsulfamoyl)benzamide 386

4-[2-(4-benzhydrylpiperazin-1-yl)-2-oxo-ethyl]-5-cyclopropyl-2-fluoro-N-methylsulfonyl-benzamide 387

trans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)benzamide 388

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(4-methylcyclohexyl)methoxy]benzamide 389

5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-[(6-methylspiro[2.5]octan-6-yl)methoxy]benzamide 390

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(6-methylspiro[2.5]octan-6-yl)methoxy]benzamide 391

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-(norcaran-3-ylmethoxy)benzamide 392

5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-(norcaran-3-ylmethoxy)benzamide 393

cis-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)benzamide 394

5-cyclopropyl-2-fluoro-N-(3-fluoroazetidin-1-yl)sulfonyl-4-(norcaran-3-ylmethoxy)benzamide 395

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(2,6-dimethylcyclohexyl)methoxy]-2-fluoro-benzamide 396

N-(azetidin-1-ylsulfonyl)-5-chloro-4-[(2,6-dimethylcyclohexyl)methoxy]-2-fluoro-benzamide 397

5-chloro-N-cyclopropylsulfonyl-4-[(2,6-dimethylcyclohexyl)methoxy]-2-fluoro-benzamide 398

trans-4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(2-methylcyclopropyl)benzamide 399

4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-[(E)-prop-1-enyl]benzamide 400

5-chloro-N-ethylsulfonyl-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide 401

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(3,3-difluorocyclohexyl)methoxy]-2-fluoro-benzamide 402

5-cyclopropyl-4-[(3,3-difluorocyclohexyl)methoxy]-2-fluoro-N-methylsulfonyl-benzamide 403

5-cyclopropyl-4-[(3,3-difluorocyclohexyl)methoxy]-2-fluoro-N-(methylsulfamoyl)benzamide 404

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(3,3-difluorocyclohexyl)methoxy]-2-fluoro-benzamide 405

5-cyclopropyl-4-[(3,3-difluorocyclohexyl)methoxy]-2-fluoro-N-(methylsulfamoyl)benzamide 406

5-cyclopropyl-4-[(3,3-difluorocyclohexyl)methoxy]-2-fluoro-N-methylsulfonyl-benzamide 407

4-[[1-[(4-chlorophenyl)-phenyl-methyl]azetidin-3-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonyl- benzamide 408

4-[[1-[(3-chlorophenyl)-phenyl-methyl]azetidin-3-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonyl- benzamide 409

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-[[1-(phenyl-[3-(trifluoromethoxy)phenyl)methyl]azetidin-3- yl]methoxy]benzamide 410

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-[[1-[phenyl-[4-(trifluoromethoxy)phenyl]methyl]azetidin-3- yl]methoxy]benzamide 411

4-[(1-benzhydryl-4-piperidyl)methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonyl-benzamide 412

5-cyclopropyl-N-ethylsulfonyl-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide 413

5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-[(4-methylcyclohexyl)methoxy]benzamide 414

5-cyclopropyl-2-fluoro-4-[(4-methylcyclohexyl)methoxy]-N-methylsulfonyl- benzamide 415

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(4-cyclopropylcyclohex-3-en-1-yl)methoxy]-2-fluoro- benzamide 416

5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(((2s,3aR,4S,7R,7aS)-octahydro-1H-4,7-methanoinden-2-yl)methoxy)benzamide 417

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((trans-5-methoxyadamantan-2-yl)oxy)benzamide 418

5-cyclopropyl-N-cyclpropylsulfonyl-2-fluoro-4-[(1-methylcyclohex-3-en-1-yl)methoxy]benzamide 419

5-cyclopropyl-2-fluoro-4-[(6-methylspiro[2.5]octan-6-yl)methoxy]-N-methylsulfonyl-benzamide 420

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[(4-methylcyclohexyl)methoxy]benzamide 421

5-cyclopropyl-4-[[1- (difluoromethyl)cyclohexyl]methoxy]-2-fluoro-N-methylsulfonyl-benzamide 422

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[[1-(difluoromethyl)cyclohexyl]methoxy]-2-fluoro- benzamide 423

N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((trans-5-methoxyadamantan-2-yl)oxy)benzamide 424

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(2,2-difluoro-6-methyl-spiro[2.5]octan-6-yl)methoxy]-2- fluoro-benzamide 425

5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-[[1-methyl-4-(trifluoromethyl)cyclohexyl]methoxy]benzamide 426

5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-[[1- methyl-4-(trifluoromethyl)cyclohexyl]methoxy]benzamide 427

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[[1- methyl-4-(trifluoromethyl)cyclohexyl]methoxy]benzamide 428

5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-[[4-(trifluoromethyl)cyclohexyl]methoxy]benzamide 429

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-[[4-(trifluoromethyl)cyclohexyl]methoxy]benzamide 430

5-cyclopropyl-N-cyclopropylsulfonyl-4-[(7,7-difluoronorcaran-1-yl)methoxy]-2-fluoro-benzamide 431

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[(7,7-difluoronorcaran-1-yl)methoxy]-2-fluoro-benzamide 432

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-(norcaran-3-ylmethoxy)benzamide 433

5-cyclopropyl-N-cyclopropylsulfonyl-4-[(7,7-difluoronorcaran-1-yl)methoxy]-2-fluoro-benzamide 434

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-[7,7-difluoronorcaran-1-yl)methoxy]-2-fluoro-benzamide 435

5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4- (((1r,4r)-4-(trifluoromethyl)cyclohexyl)methoxy)benzamide 436

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4- (((1r,4r)-4-(trifluoromethyl)cyclohexyl)methoxy)benzamide 437

4-((1-benzoylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide 438

5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenylsulfonyl)azetidin-3-yl)methoxy)benzamide 439

4-(1-benzhydrylazetidin-3-yloxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide 440

4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide 441

4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-N-(ethylsulfonyl)-2-fluorobenzamide 442

5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((3,3-difluorocyclohexyl)methoxy)-2-fluorobenzamide 443

5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((3,3-difluorocyclohexyl)methoxy)-2-fluorobenzamide 444

4-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-((3,3-difluoroazetidin-1-yl)sulfonyl)-2-fluorobenzamide 445

5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((2s,3aR,4S,7R,7aS)-octahydro-1H-4,7-methanoinden-2-yl)methoxy)benzamide 446

5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzamide 447

5-cyclopropyl-2-fluoro-N-((3-fluoroazetidin-1- yl)sulfonyl)-4-((1-methylcyclohexyl)methoxy)benzamide 448

N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzamide 449

5-chloro-N-(cyclopropylsulfonyl)-4-((7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2- fluorobenzamide 450

(1s,3R,4r,5S,7s)-methyl 4-(2-chloro-5-fluoro-4-((methy-lsulfonyl)carbamoyl)-phenoxy)adamantane-1- carboxylate 451

(1s,3R,4s,5S,7s)-methyl 4-(2-chloro-5-fluoro-4-((methylsulfonyl)-carbanoyl)-phenoxy)adamantane-1- carboxylate 452

(1s,3R,4r,5S,7s)-methyl 4-(2-chloro-5-fluoro-4-((N-methylsulfamoyl)-carbamoyl)phenoxy)adamantane-1- carboxylate 453

(1s,3R,4s,5S,7s)-methyl 4-(2-chloro-5-fluoro-4-((N-methylsulfamoyl)carbamoyl)-phenoxy)adamantane-1- carboxylate 454

(N-(azetidin-1-ylsulfonyl)-4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide 455

4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluoro-N-(methylsulfonyl)benzamide

Synthesis of Compounds

Compounds of formula (I), wherein X¹ is O, S, or NH, may be prepared bythe process illustrated in Scheme 1.

Compounds of formula (I) can be made from compounds of formula (II) bydisplacement with formula (III) and a base (reaction step ii in Scheme1). Suitable conditions include potassium tert-butoxide in DMSO, NaH inDMF or K₂CO₃ in DMF. Formula (II) can be made according to step (i) byactivation of the acid group of formula (IV) with reagents such asoxalyl chloride, carbonyl di-imidazole (CDl), propylphosphonicanhydride, a uronium based amide coupling agent or a carbodiimidereagent followed by displacement with a sulfonamide of formula (VII) inthe presence of a nucleophilic base such as

-   4-dimethylaminopyridine. Illustrative conditions comprise N,-   N-dimethylaminopropyl-N-ethylcarbodiimide and    4-dimethylaminopyridine with N,-   N-diisopropylethylamine.

Alternatively, compounds of formula (I) can be made from compounds offormula (IV) by reversing steps (i) and (ii) as described in Scheme 1.Illustrative conditions for steps vi and vii are as previously describedin steps (ii) and (i), respectively.

Compounds of formula (I) can also be made from compounds of formula (V)according to step (v) by displacement of the ester with compounds offormula (VII) and a suitable base such as potassium tert-butoxide, NaHor DBU. Compounds of formula (I) can also be made from compounds offormula (v) by a two steps sequence (see steps viii and vii in Scheme1). Compounds of formula (V) can be made from compounds of formula(VIII) according to step (iv) via a nucleophilic substitution reactionusing compounds of formula (III) and a base as described in step ii.Compounds of formula (VIII) can be made from compounds of formula (IV)according to step (iii) using protecting group methodology as describedin references such as ‘Greene's Protective Groups in Organic Synthesis’.When Pg is tolyl, illustrative conditions comprise thionyl chloride orcarbonyldiimidazole with para-cresol. When Pg is tert-butyl,illustrative conditions comprise di-tert butyl dicarbonate and4-dimethylaminopyridine in tert-butanol.

Compounds of formula (I), wherein R⁵ is Ar, heteroaryl, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₁₋₈ alkoxy, C₃₋₁₀ cycloalkyl or C₂₋₉ heterocycloalkyl can beprepared by the process illustrated in Scheme 2. In certain embodiment,W groups in compounds of formula (IX, X and XI) are an ester or cyanogroup.

Compounds of formula (I) can be prepared from compounds of formulae(XII)

(—V═OH) according to reaction step (iv) by activation of the acid groupwith reagents such as oxalyl chloride, carbonyl di-imidazole (CDl), auronium based amide coupling agent, propylphosphonic anhydride or acarbodiimide reagent followed by displacement with a suitablesulfonamide of formula (VII) in the presence of a nucleophilic base suchas 4-dimethylaminopyridine.

Alternatively, compounds of formula (I) can be prepared from compoundsof formula (XII) (—V═NH₂) according to reaction step (v) by displacementof a sulfonyl chloride of formula (XIII) under basic reactionconditions.

Compounds of formula (X11) can be prepared by hydrolysis of the nitrilefunctional group in compounds of formula (XI, W═CN) or by hydrosis ofthe ester functional group in compounds of formula (X1, W═CO₂Pg) byeither acidic or basic methods according to step (iii) as required.

Compounds of formula (XI) can be prepared from compounds of formula (X)by palladium-catalyzed coupling of a compound of formula (R₅M) accordingto step (ii).

Conveniently the coupling is effective with a boronic acid or ester offormula (R₅M). The coupling reaction can be carried out with a varietyof palladium catalysts such as palladium acetate ortetrakistriphenylphosphine palladium (0) in various solvents and in thepresence of bases such as sodium and potassium carbonate, cesiumfluoride or potassium phosphate. Compounds of formula (X) can beprepared under similar conditions as described for the preparation ofcompounds of formula (V), (VI) and (I) in Scheme 1.

B. Pharmaceutical Compositions and Administration

In addition to one or more of the compounds provided above (orstereoisomers, geometric isomers, tautomers, solvates, metabolites,isotopes, pharmaceutically acceptable salts, or prodrugs thereof), theinvention also provides for compositions and medicaments comprising acompound of Formula I or and embodiment thereof and at least onepharmaceutically acceptable carrier, diluent or excipient. Thecompositions of the invention can be used to selectively inhibit NaV1.7in patients (e.g, humans).

The term “composition,” as used herein, is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In one embodiment, the invention provides for pharmaceuticalcompositions (or medicaments) comprising a compound of Formula I or anembodiment thereof, and its stereoisomers, geometric isomers, tautomers,solvates, metabolites, isotopes, pharmaceutically acceptable salts, orprodrugs thereof) and a pharmaceutically acceptable carrier, diluent orexcipient. In another embodiment, the invention provides for preparingcompositions (or medicaments) comprising compounds of the invention. Inanother embodiment, the invention provides for administering compoundsof Formula I or its embodiments and compositions comprising compounds ofFormula I or an embodiment thereof to a patient (e.g., a human patient)in need thereof.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The effective amount of the compound tobe administered will be governed by such considerations, and is theminimum amount necessary to inhibit NaV1.7 activity as required toprevent or treat the undesired disease or disorder, such as for example,pain. For example, such amount may be below the amount that is toxic tonormal cells, or the mammal as a whole.

In one example, the therapeutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.01-100 mg/kg, alternatively about e.g., 0.1 to 20 mg/kg ofpatient body weight per day, with the typical initial range of compoundused being 0.3 to 15 mg/kg/day. The daily does is, in certainembodiments, given as a single daily dose or in divided doses two to sixtimes a day, or in sustained release form. In the case of a 70 kg adulthuman, the total daily dose will generally be from about 7 mg to about1,400 mg. This dosage regimen may be adjusted to provide the optimaltherapeutic response. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, intracerebral, intraocular, intralesional orsubcutaneous administration.

The compositions comprising compounds of Formula I or an embodimentthereof are normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. A typicalformulation is prepared by mixing a compound of the present inventionand a diluent, carrier or excipient. Suitable diluents, carriers andexcipients are well known to those skilled in the art and are describedin detail in, e.g., Ansel, Howard C., et al., Ansel's PharmaceuticalDosage Forms and Drug Delivery Systems. Philadelphia: Lippincott,Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: TheScience and Practice of Pharmacy. Philadelphia: Lippincott, Williams &Wilkins, 2000; and Rowe, Raymond C. Handbook of PharmaceuticalExcipients. Chicago, Pharmaceutical Press, 2005. The formulations mayalso include one or more buffers, stabilizing agents, surfactants,wetting agents, lubricating agents, emulsifiers, suspending agents,preservatives, antioxidants, opaquing agents, glidants, processing aids,colorants, sweeteners, perfuming agents, flavoring agents, diluents andother known additives to provide an elegant presentation of the drug(i.e., a compound of the present invention or pharmaceutical compositionthereof) or aid in the manufacturing of the pharmaceutical product(i.e., medicament).

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water and the like. The particularcarrier, diluent or excipient used will depend upon the means andpurpose for which a compound of the present invention is being applied.Solvents are generally selected based on solvents recognized by personsskilled in the art as safe (GRAS) to be administered to a mammal. Ingeneral, safe solvents are non-toxic aqueous solvents such as water andother non-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Theformulations can also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Aactive pharmaceutical ingredient of the invention (e.g., compound ofFormula I or an embodiment thereof) can also be entrapped inmicrocapsules prepared, for example, by coacervation techniques or byinterfacial polymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philidelphia, Pa.

Sustained-release preparations of a compound of the invention (e.g.,compound of Formula I or an embodiment thereof) can be prepared.Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula I or an embodiment thereof, which matrices are inthe form of shaped articles, e.g., films, or microcapsules. Examples ofsustained-release matrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983),non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater.Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers suchas the LUPRON DEPOT™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate) andpoly-D-(−)-3-hydroxybutyric acid (EP 133,988A). Sustained releasecompositions also include liposomally entrapped compounds, which can beprepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci.U.S.A. 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A.77:4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A).Ordinarily, the liposomes are of the small (about 200-800 Angstroms)unilamelar type in which the lipid content is greater than about 30 mol% cholesterol, the selected proportion being adjusted for the optimaltherapy.

The formulations include those suitable for the administration routesdetailed herein. The formulations can conveniently be presented in unitdosage form and can be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(St) Edition, Lippincott Williams &Wilkins, Philidelphia, PA. Such methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more accessory ingredients.

In general the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers,diluents or excipients or finely divided solid carriers, diluents orexcipients, or both, and then, if necessary, shaping the product. Atypical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. The formulations can beprepared using conventional dissolution and mixing procedures. Forexample, the bulk drug substance (i.e., compound of the presentinvention or stabilized form of the compound (e.g., complex with acyclodextrin derivative or other known complexation agent) is dissolvedin a suitable solvent in the presence of one or more of the excipientsdescribed above. A compound of the present invention is typicallyformulated into pharmaceutical dosage forms to provide an easilycontrollable dosage of the drug and to enable patient compliance withthe prescribed regimen.

In one example, compounds of Formula I or an embodiment thereof may beformulated by mixing at ambient temperature at the appropriate pH, andat the desired degree of purity, with physiologically acceptablecarriers, i.e., carriers that are non-toxic to recipients at the dosagesand concentrations employed into a galenical administration form. The pHof the formulation depends mainly on the particular use and theconcentration of compound, but preferably ranges anywhere from about 3to about 8. In one example, a compound of Formula I (or an embodimentthereof) is formulated in an acetate buffer, at pH 5. In anotherembodiment, the compounds of Formula I or an embodiment thereof aresterile. The compound may be stored, for example, as a solid oramorphous composition, as a lyophilized formulation or as an aqueoussolution.

Formulations of a compound of the invention (e.g., compound of Formula Ior an embodiment thereof) suitable for oral administration can beprepared as discrete units such as pills, capsules, cachets or tabletseach containing a predetermined amount of a compound of the invention.

Compressed tablets can be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets can bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets canoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs can be prepared for oral use. Formulationsof a compound of the invention (e.g., compound of Formula I or anembodiment thereof) intended for oral use can be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions can contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients can be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets can be uncoated or can be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax can be employed.

An example of a suitable oral administration form is a tablet containingabout 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250mg, 300 mg and 500 mg of the compound of the invention compounded withabout 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose,about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mgmagnesium stearate. The powdered ingredients are first mixed togetherand then mixed with a solution of the PVP. The resulting composition canbe dried, granulated, mixed with the magnesium stearate and compressedto tablet form using conventional equipment. An example of an aerosolformulation can be prepared by dissolving the compound, for example5-400 mg, of the invention in a suitable buffer solution, e.g. aphosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride,if desired. The solution may be filtered, e.g., using a 0.2 micronfilter, to remove impurities and contaminants.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientcan be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients can be formulated in a creamwith an oil-in-water cream base. If desired, the aqueous phase of thecream base can include a polyhydric alcohol, i.e., an alcohol having twoor more hydroxyl groups such as propylene glycol, butane 1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)and mixtures thereof. The topical formulations can desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethyl sulfoxide and relatedanalogs.

The oily phase of the emulsions of this invention can be constitutedfrom known ingredients in a known manner. While the phase can comprisemerely an emulsifier, it desirably comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

In one aspect of topical applications, it is desired to administer aneffective amount of a pharmaceutical composition according to theinvention to target area, e.g., skin surfaces, mucous membranes, and thelike, which are adjacent to peripheral neurons which are to be treated.This amount will generally range from about 0.0001 mg to about 1 g of acompound of the invention per application, depending upon the area to betreated, whether the use is diagnostic, prophylactic or therapeutic, theseverity of the symptoms, and the nature of the topical vehicleemployed. A preferred topical preparation is an ointment, wherein about0.001 to about 50 mg of active ingredient is used per cc of ointmentbase. The pharmaceutical composition can be formulated as transdermalcompositions or transdermal delivery devices (“patches”). Suchcompositions include, for example, a backing, active compound reservoir,a control membrane, liner and contact adhesive. Such transdermal patchesmay be used to provide continuous pulsatile, or on demand delivery ofthe compounds of the present invention as desired.

Aqueous suspensions of a compound of the invention (e.g., compound ofFormula I or an embodiment thereof) contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth and gum acacia, and dispersing or wetting agents such asa naturally occurring phosphatide (e.g., lecithin), a condensationproduct of an alkylene oxide with a fatty acid (e.g., polyoxyethylenestearate), a condensation product of ethylene oxide with a long chainaliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

Formulations of a compound of the invention (e.g., compound of Formula Ior an embodiment thereof) can be in the form of a sterile injectablepreparation, such as a sterile injectable aqueous or oleaginoussuspension. This suspension can be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, such as a solution in1,3-butanediol or prepared as a lyophilized powder. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile fixed oilscan conventionally be employed as a solvent or suspending medium. Forthis purpose any bland fixed oil can be employed including syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid canlikewise be used in the preparation of injectables.

The amount of active ingredient that can be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans cancontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which can varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion can contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which can contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which can include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration can be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration can beprepared according to conventional methods and can be delivered withother therapeutic agents such as compounds heretofore used in thetreatment of disorders as described below.

The formulations can be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

When the binding target is located in the brain, certain embodiments ofthe invention provide for a compound of formula I (or an embodimentthereof) to traverse the blood-brain barrier. Certain neurodegenerativediseases are associated with an increase in permeability of theblood-brain barrier, such that a compound of formula I (or an embodimentthereof) can be readily introduced to the brain. When the blood-brainbarrier remains intact, several art-known approaches exist fortransporting molecules across it, including, but not limited to,physical methods, lipid-based methods, and receptor and channel-basedmethods.

Physical methods of transporting a compound of formula I (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, circumventing the blood-brain barrier entirely, or bycreating openings in the blood-brain barrier.

Circumvention methods include, but are not limited to, direct injectioninto the brain (see, e.g., Papanastassiou et al., Gene Therapy9:398-406, 2002), interstitial infusion/convection-enhanced delivery(see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91:2076-2080,1994), and implanting a delivery device in the brain (see, e.g., Gill etal., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford.

Pharmaceutical). Methods of creating openings in the barrier include,but are not limited to, ultrasound (see, e.g., U.S. Patent PublicationNo. 2002/0038086), osmotic pressure (e.g., by administration ofhypertonic mannitol (Neuwelt, E. A., Implication of the Blood-BrainBarrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y.,1989)), and permeabilization by, e.g., bradykinin or permeabilizer A-7(see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and5,686,416).

Lipid-based methods of transporting a compound of formula I (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, encapsulating the a compound of formula I (or an embodimentthereof) in liposomes that are coupled to antibody binding fragmentsthat bind to receptors on the vascular endothelium of the blood-brainbarrier (see, e.g., U.S. Patent Application Publication No.2002/0025313), and coating a compound of formula I (or an embodimentthereof) in low-density lipoprotein particles (see, e.g., U.S. PatentApplication Publication No. 2004/0204354) or apolipoprotein E (see,e.g., U.S. Patent Application Publication No. 2004/0131692).

Receptor and channel-based methods of transporting a compound of formulaI (or an embodiment thereof) across the blood-brain barrier include, butare not limited to, using glucocorticoid blockers to increasepermeability of the blood-brain barrier (see, e.g., U.S. PatentApplication Publication Nos. 2002/0065259, 2003/0162695, and2005/0124533); activating potassium channels (see, e.g., U.S. PatentApplication Publication No. 2005/0089473), inhibiting ABC drugtransporters (see, e.g., U.S. Patent Application Publication No.2003/0073713); coating a compound of formula I (or an embodimentthereof) with a transferrin and modulating activity of the one or moretransferrin receptors (see, e.g., U.S. Patent Application PublicationNo. 2003/0129186), and cationizing the antibodies (see, e.g., U.S. Pat.No. 5,004,697).

For intracerebral use, in certain embodiments, the compounds can beadministered continuously by infusion into the fluid reservoirs of theCNS, although bolus injection may be acceptable. The inhibitors can beadministered into the ventricles of the brain or otherwise introducedinto the CNS or spinal fluid. Administration can be performed by use ofan indwelling catheter and a continuous administration means such as apump, or it can be administered by implantation, e.g., intracerebralimplantation of a sustained-release vehicle. More specifically, theinhibitors can be injected through chronically implanted cannulas orchronically infused with the help of osmotic minipumps. Subcutaneouspumps are available that deliver proteins through a small tubing to thecerebral ventricles. Highly sophisticated pumps can be refilled throughthe skin and their delivery rate can be set without surgicalintervention. Examples of suitable administration protocols and deliverysystems involving a subcutaneous pump device or continuousintracerebroventricular infusion through a totally implanted drugdelivery system are those used for the administration of dopamine,dopamine agonists, and cholinergic agonists to Alzheimer's diseasepatients and animal models for Parkinson's disease, as described byHarbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al.,Mov. Disord. 2: 143, 1987.

A compound of formula I (or an embodiment thereof) used in the inventionare formulated, dosed, and administered in a fashion consistent withgood medical practice. Factors for consideration in this context includethe particular disorder being treated, the particular mammal beingtreated, the clinical condition of the individual patient, the cause ofthe disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. A compound of formula I (or anembodiment thereof) need not be, but is optionally formulated with oneor more agent currently used to prevent or treat the disorder inquestion. The effective amount of such other agents depends on theamount of a compound of the invention present in the formulation, thetype of disorder or treatment, and other factors discussed above.

These are generally used in the same dosages and with administrationroutes as described herein, or about from 1 to 99% of the dosagesdescribed herein, or in any dosage and by any route that isempirically/clinically determined to be appropriate.

For the prevention or treatment of disease, the appropriate dosage of acompound of formula I (or an embodiment thereof) (when used alone or incombination with other agents) will depend on the type of disease to betreated, the properties of the compound, the severity and course of thedisease, whether the compound is administered for preventive ortherapeutic purposes, previous therapy, the patient's clinical historyand response to the compound, and the discretion of the attendingphysician. The compound is suitably administered to the patient at onetime or over a series of treatments. Depending on the type and severityof the disease, about 1 μg/kg to 15 mg/kg (e.g., 0.1 mg/kg-10 mg/kg) ofcompound can be an initial candidate dosage for administration to thepatient, whether, for example, by one or more separate administrations,or by continuous infusion. One typical daily dosage might range fromabout 1 μg kg to 100 mg/kg or more, depending on the factors mentionedabove. For repeated administrations over several days or longer,depending on the condition, the treatment would generally be sustaineduntil a desired suppression of disease symptoms occurs. One exemplarydosage of a compound of formula I (or an embodiment thereof) would be inthe range from about 0.05 mg/kg to about 10 mg/kg. Thus, one or moredoses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, or 10 mg/kg (or anycombination thereof) may be administered to the patient. Such doses maybe administered intermittently, e.g., every week or every three weeks(e.g., such that the patient receives from about two to about twenty,or, e.g., about six doses of the antibody). An initial higher loadingdose, followed by one or more lower doses may be administered. Anexemplary dosing regimen comprises administering an initial loading doseof about 4 mg/kg, followed by a weekly maintenance dose of about 2 mg kgof the compound. However, other dosage regimens may be useful. Theprogress of this therapy is easily monitored by conventional techniquesand assays.

Other typical daily dosages might range from, for example, about 1 g/kgto up to 100 mg/kg or more (e.g., about 1 μg kg to 1 mg/kg, about 1μg/kg to about 5 mg/kg, about 1 mg kg to 10 mg/kg, about 5 mg/kg toabout 200 mg/kg, about 50 mg/kg to about 150 mg/mg, about 100 mg/kg toabout 500 mg/kg, about 100 mg/kg to about 400 mg/kg, and about 200 mg/kgto about 400 mg/kg), depending on the factors mentioned above.Typically, the clinician will administer a compound until a dosage isreached that results in improvement in or, optimally, elimination of,one or more symptoms of the treated disease or condition. The progressof this therapy is easily monitored by conventional assays. One or moreagent provided herein may be administered together or at different times(e.g., one agent is administered prior to the administration of a secondagent). One or more agent may be administered to a subject usingdifferent techniques (e.g., one agent may be administered orally, whilea second agent is administered via intramuscular injection orintranasally). One or more agent may be administered such that the oneor more agent has a pharmacologic effect in a subject at the same time.Alternatively, one or more agent may be administered, such that thepharmacological activity of the first administered agent is expiredprior the administration of one or more secondarily administered agents(e.g., 1, 2, 3, or 4 secondarily administered agents).

C. Indications and Methods of Treatment

The compounds of the invention modulate, preferably inhibit, ion fluxthrough a voltage-dependent sodium channel in a mammal, (e.g, a human).Any such modulation, whether it be partial or complete inhibition orprevention of ion flux, is sometimes referred to herein as “blocking”and corresponding compounds as “blockers” or “inhibitors”. In general,the compounds of the invention modulate the activity of a sodium channeldownwards by inhibiting the voltage-dependent activity of the sodiumchannel, and/or reduce or prevent sodium ion flux across a cell membraneby preventing sodium channel activity such as ion flux.

The compounds of the invention inhibit the ion flux through avoltage-dependent sodium channel. In one aspect, the compounds are stateor frequency dependent modifers of the sodium channels, having a lowaffinity for the rested/closed state and a high affinity for theinactivated state. Without being bound by any particular theory, it isthought that these compounds are likely to interact with overlappingsites located in the inner cavity of the sodium conducting pore of thechannel similar to that described for other state-dependent sodiumchannel blockers (Cestèle, S., et al., op. cit.). These compounds mayalso be likely to interact with sites outside of the inner cavity andhave allosteric effects on sodium ion conduction through the channelpore.

Any of these consequences may ultimately be responsible for the overalltherapeutic benefit provided by these compounds.

Accordingly, the compounds of the invention are sodium channel blockersand are therefore useful for treating diseases and conditions inmammals, for example humans, and other organisms, including all thosediseases and conditions which are the result of aberrantvoltage-dependent sodium channel biological activity or which may beameliorated by modulation of voltage-dependent sodium channel biologicalactivity. In particular, the compounds of the invention, i.e., thecompounds of formula (I) and embodiments and (or stereoisomers,geometric isomers, tautomers, solvates, metabolites, isotopes,pharmaceutically acceptable salts, or prodrugs thereof), are useful fortreating diseases and conditions in mammals, for example humans, whichare the result of aberrant voltage-dependent NaV1.7 biological activityor which may be ameliorated by the modulation, preferably theinhibition, of NaV1.7 biological activity. In certain aspects, thecompounds of the invention selectively inhibit NaV1.7 over NaV1.5.

As defined herein, a sodium channel-mediated disease or condition refersto a disease or condition in a mammal, preferably a human, which isameliorated upon modulation of the sodium channel and includes, but isnot limited to, pain, central nervous conditions such as epilepsy,anxiety, depression and bipolar disease; cardiovascular conditions suchas arrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome and muscleparalysis or tetanus; neuroprotection against stroke, neural trauma andmultiple sclerosis; and channelopathies such as erythromyalgia andfamilial rectal pain syndrome.

In one aspect, the present invention relates to compounds,pharmaceutical compositions and methods of using the compounds andpharmaceutical compositions for the treatment of sodium channel-mediateddiseases in mammals, preferably humans and preferably diseases andconditions related to pain, central nervous conditions such as epilepsy,anxiety, depression and bipolar disease; cardiovascular conditions suchas arrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome and muscleparalysis or tetanus; neuroprotection against stroke, neural trauma andmultiple sclerosis; and channelopathies such as erythromyalgia andfamilial rectal pain syndrome, by administering to a mammal, for examplea human, in need of such treatment an effective amount of a sodiumchannel blocker modulating, especially inhibiting, agent.

A sodium channel-mediated disease or condition also includes painassociated with HIV, HIV treatment induced neuropathy, trigeminalneuralgia, glossopharyngeal neuralgia, neuropathy secondary tometastatic infiltration, adiposis dolorosa, thalamic lesions,hypertension, autoimmune disease, asthma, drug addiction (e.g., opiate,benzodiazepine, amphetamine, cocaine, alcohol, butane inhalation),Alzheimer, dementia, age-related memory impairment, Korsakoff syndrome,restenosis, urinary dysfunction, incontinence, Parkinson's disease,cerebrovascular ischemia, neurosis, gastrointestinal disease, sicklecell anemia, transplant rejection, heart failure, myocardial infarction,reperfusion injury, intermittant claudication, angina, convulsion,respiratory disorders, cerebral or myocardial ischemias, long-QTsyndrome, Catecholeminergic polymorphic ventricular tachycardia,ophthalmic diseases, spasticity, spastic paraplegia, myopathies,myasthenia gravis, paramyotonia congentia, hyperkalemic periodicparalysis, hypokalemic periodic paralysis, alopecia, anxiety disorders,psychotic disorders, mania, paranoia, seasonal affective disorder, panicdisorder, obsessive compulsive disorder (OCD), phobias, autism,Aspergers Syndrome, Retts syndrome, disintegrative disorder, attentiondeficit disorder, aggressivity, impulse control disorders, thrombosis,pre clampsia, congestive cardiac failure, cardiac arrest, Freidrich'sataxia, Spinocerebellear ataxia, myelopathy, radiculopathy, systemiclupus erythamatosis, granulomatous disease, olivo-ponto-cerebellaratrophy, spinocerebellar ataxia, episodic ataxia, myokymia, progressivepallidal atrophy, progressive supranuclear palsy and spasticity,traumatic brain injury, cerebral oedema, hydrocephalus injury, spinalcord injury, anorexia nervosa, bulimia, Prader-Willi syndrome, obesity,optic neuritis, cataract, retinal haemorrhage, ischaemic retinopathy,retinitis pigmentosa, acute and chronic glaucoma, macular degeneration,retinal artery occlusion, Chorea, Huntington's chorea, cerebral edema,proctitis, post-herpetic neuralgia, eudynia, heat sensitivity,sarcoidosis, irritable bowel syndrome, Tourette syndrome, Lesch-NyhanSyndrome, Brugado syndrome, Liddle syndrome, Crohns disease, multiplesclerosis and the pain associated with multiple sclerosis (MS),amyotrophic lateral sclerosis (ALS), disseminated sclerosis, diabeticneuropathy, peripheral neuropathy, charcot marie tooth syndrome,arthritic, rheumatoid arthritis, osteoarthritis, chondrocalcinosis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,myotonic dystrophy, muscular dystrophy, malignant hyperthermia, cysticfibrosis, pseudoaldosteronism, rhabdomyolysis, mental handicap,hypothyroidism, bipolar depression, anxiety, schizophrenia, sodiumchannel toxin related illnesses, familial erythromelalgia, primaryerythromelalgia, rectal pain, cancer, epilepsy, partial and generaltonic seizures, febrile seizures, absence seizures (petit mal),myoclonic seizures, atonic seizures, clonic seizures, Lennox Gastaut,West Syndome (infantile spasms), multiresistant seizures, seizureprophylaxis (anti-epileptogenic), familial Mediterranean fever syndrome,gout, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotectionunder ischaemic conditions caused by stroke or neural trauma,tachy-arrhythmias, atrial fibrillation and ventricular fibrillation andas a general or local anaesthetic.

As used herein, the term “pain” refers to all categories of pain and isrecognized to include, but is not limited to, neuropathic pain,inflammatory pain, nociceptive pain, idiopathic pain, neuralgic pain,orofacial pain, burn pain, burning mouth syndrome, somatic pain,visceral pain, myofacial pain, dental pain, cancer pain, chemotherapypain, trauma pain, surgical pain, post-surgical pain, childbirth pain,labor pain, chronic regional pain syndrome (CRPS), reflex sympatheticdystrophy, brachial plexus avulsion, neurogenic bladder, acute pain(e.g., musculoskeletal and post-operative pain), chronic pain,persistent pain, peripherally mediated pain, centrally mediated pain,chronic headache, migraine headache, familial hemiplegic migraine,conditions associated with cephalic pain, sinus headache, tensionheadache, phantom limb pain, peripheral nerve injury, pain followingstroke, thalamic lesions, radiculopathy, HIV pain, post-herpetic pain,non-cardiac chest pain, irritable bowel syndrome and pain associatedwith bowel disorders and dyspepsia, and combinations thereof.

Furthermore, sodium channel blockers have clinical uses in addition topain. The present invention therefore also relates to compounds,pharmaceutical compositions and methods of using the compounds andpharmaceutical compositions for the treatment of diseases or conditionssuch as cancer and pruritus (itch).

Pruritus, commonly known as itch, is a common dermatological condition.While the exact causes of pruritus are complex and incompletelyunderstood, there has long been evidence that itch involves sensoryneurons, especially C fibers, similar to those that mediate pain(Schmelz, M., et al., J. Neurosci. (1997), 17: 8003-8). In particular,it is believed that sodium influx through voltage-gated sodium channelsis essential for the propagation of itch sensation from the skin.Transmission of the itch impulses results in the unpleasant sensationthat elicits the desire or reflex to scratch.

Multiple causes and electrical pathways for eliciting itch are known. Inhumans, pruritis can be elicited by histamine or PAR-2 agonists such asmucunain that activate distinct populations of C fibers (Namer, B., etal., J. Neurophysiol. (2008), 100: 2062-9). A variety of neurotrophicpeptides are known to mediate itch in animal models (Wang, H., andYosipovitch, G., International Journal of Dermatology (2010), 49: 1-11).Itch can also be elicited by opioids, evidence of distinct pharmacologyfrom that of pain responses.

There exists a complex interaction between itch and pain responses thatarises in part from the overlapping sensory input from the skin (Ikoma,A., et al., Arch. Dermatol. (2003), 139: 1475-8) and also from thediverse etiology of both pain and pruritis. Pain responses canexacerbate itching by enhancing central sensitization or lead toinhibition of painful scratching. Particularly severe forms of chronicitch occur when pain responses are absent, as in the case ofpost-herpetic itch (Oaklander, A. L., et al., Pain (2002), 96: 9-12).

The compounds of the invention can also be useful for treating pruritus.The rationale for treating itch with inhibitors of voltage-gated sodiumchannels, especially NaV1.7, is as follows:

1) The propagation of electrical activity in the C fibers that sensepruritinergic stimulants requires sodium entry through voltage-gatedsodium channels.2) NaV1.7 is expressed in the C fibers and kerotinocytes in human skin(Zhao, P., et al., Pain (2008), 139: 90-105).3) A gain of function mutation of NaV1.7 (L858F) that causeserythromelalgia also causes chronic itch (Li, Y., et al., Clinical andExperimental Dermatology (2009), 34: e313-e4).4) Chronic itch can be alleviated with treatment by sodium channelblockers, such as the local anesthetic lidocaine (Oaklander, A. L., etal., Pain (2002), 96: 9-12; Villamil, A. G., et al., The American

Journal of Medicine (2005), 118: 1160-3). In these reports, lidocainewas effective when administered either intravenously or topically (aLidoderm patch). Lidocaine can have multiple activities at the plasmaconcentrations achieved when administered systemically, but whenadministered topically, the plasma concentrations are only about 1 μM(Center for Drug Evaluation and Research NDA 20-612). At theseconcentrations, lidocaine is selective for sodium channel block andinhibits spontaneous electrical activity in C fibers and pain responsesin animal models (Xiao, W. H., and Bennett, G. J. Pain (2008), 137:218-28). The types of itch or skin irritation, include, but are notlimited to:

a) psoriatic pruritus, itch due to hemodyalisis, aguagenic pruritus, anditching caused by skin disorders (e.g., contact dermatitis), systemicdisorders, neuropathy, psychogenic factors or a mixture thereof;b) itch caused by allergic reactions, insect bites, hypersensitivity(e.g., dry skin, acne, eczema, psoriasis), inflammatory conditions orinjury;c) itch associated with vulvar vestibulitis; andd) skin irritation or inflammatory effect from administration of anothertherapeutic such as, for example, antibiotics, antivirals andantihistamines.

The compounds of the invention are also useful in treating certaincancers, such as hormone sensitive cancers, such as prostate cancer(adenocarcinoma), breast cancer, ovarian cancer, testicular cancer andthyroid neoplasia, in a mammal, preferably a human. The voltage gatedsodium channels have been demonstrated to be expressed in prostate andbreast cancer cells. Up-regulation of neonatal NaV1.5 occurs as anintegral part of the metastatic process in human breast cancer and couldserve both as a novel marker of the metastatic phenotype and atherapeutic target (Clin. Cancer Res. (2005), August 1; 11(15): 5381-9).Functional expression of voltage-gated sodium channel alpha-subunits,specifically NaV1.7, is associated with strong metastatic potential inprostate cancer (CaP) in vitro. Voltage-gated sodium channelalpha-subunits immunostaining, using antibodies specific to the sodiumchannel alpha subunit was evident in prostatic tissues and markedlystronger in CaP vs non-CaP patients (Prostate Cancer Prostatic Dis.,2005; 8(3):266-73). See also Diss, J. K. J., et al., Mol. Cell.Neurosci. (2008), 37:537-547 and Kis-Toth, K., et al., The Journal ofImmunology (2011), 187:1273-1280.

In consideration of the above, in one embodiment, the present inventionprovides a method for treating a mammal for, or protecting a mammal fromdeveloping, a sodium channel-mediated disease, especially pain,comprising administering to the mammal, especially a human, in needthereof, a therapeutically effective amount of a compound of theinvention or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention wherein the compoundmodulates the activity of one or more voltage-dependent sodium channels.

In another embodiment of the invention is a method of treating a diseaseor a condition in a mammal, preferably a human, wherein the disease orcondition is selected from the group consisting of pain, depression,cardiovascular diseases, respiratory diseases, and psychiatric diseases,and combinations thereof, and wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount of anembodiment of a compound of the invention, as set forth above, as astereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

One embodiment of this embodiment is wherein the disease or condition isselected from the group consisting of neuropathic pain, inflammatorypain, visceral pain, cancer pain, chemotherapy pain, trauma pain,surgical pain, post surgical pain, childbirth pain, labor pain,neurogenic bladder, ulcerative colitis, chronic pain, persistent pain,peripherally mediated pain, centrally mediated pain, chronic headache,migraine headache, sinus headache, tension headache, phantom limb pain,peripheral nerve injury, and combinations thereof.

Another embodiment of this embodiment is wherein the disease orcondition is selected from the group consisting of pain associated withHIV, HIV treatment induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritablebowel syndrome, Crohns disease, pain associated with multiple sclerosis(MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy,peripheral neuropathy, arthritic, rheumatoid arthritis, osteoarthritis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,malignant hyperthermia, cystic fibrosis, pseudoaldosteronism,rhabdomyolysis, hypothyroidism, bipolar depression, anxiety,schizophrenia, sodium channel toxin related illnesses, familialerythromelalgia, primary erythromelalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscaused by stroke or neural trauma, tachy arrhythmias, atrialfibrillation and ventricular fibrillation.

Another embodiment of the invention is a method of treating, but notpreventing, pain in a mammal, wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount of acompound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

One embodiment of this embodiment is a method wherein the pain isselected from the group consisting of neuropathic pain, inflammatorypain, visceral pain, cancer pain, chemotherapy pain, trauma pain,surgical pain, post surgical pain, childbirth pain, labor pain, dentalpain, chronic pain, persistent pain, peripherally mediated pain,centrally mediated pain, chronic headache, migraine headache, sinusheadache, tension headache, phantom limb pain, peripheral nerve injury,trigeminal neuralgia, post herpetic neuralgia, eudynia, familialerythromelalgia, primary erythromelalgia, familial rectal pain orfibromyalgia, and combinations thereof.

Another embodiment of this embodiment is a method wherein the pain isassociated with a disease or condition selected from HIV, HIV treatmentinduced neuropathy, heat sensitivity, tosarcoidosis, irritable bowelsyndrome, Crohns disease, multiple sclerosis, amyotrophic lateralsclerosis, diabetic neuropathy, peripheral neuropathy, rheumatoidarthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia,myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis,pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression,anxiety, schizophrenia, sodium channel toxin related illnesses,neurogenic bladder, ulcerative colitis, cancer, epilepsy, partial andgeneral tonic seizures, restless leg syndrome, arrhythmias, ischaemicconditions caused by stroke or neural trauma, tachy arrhythmias, atrialfibrillation and ventricular fibrillation.

Another embodiment of the invention is the method of treating pain in amammal, preferably a human, by the inhibition of ion flux through avoltage dependent sodium channel in the mammal, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of an embodiment of a compound of the invention, as setforth above, as a stereoisomer, enantiomer or tautomer thereof ormixtures thereof, or a pharmaceutically acceptable salt, solvate orprodrug thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer or tautomer thereof ormixtures thereof, or a pharmaceutically acceptable salt, solvate orprodrug thereof, and a pharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating pruritusin a mammal, preferably a human, wherein the method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of an embodiment of a compound of the invention, as set forthabove, as a stereoisomer, enantiomer or tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention, as set forth above, asa stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating cancer ina mammal, preferably a human, wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount of anembodiment of a compound of the invention, as set forth above, as astereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of decreasing ion fluxthrough a voltage dependent sodium channel in a cell in a mammal,wherein the method comprises contacting the cell with an embodiment of acompound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof.

Another embodiment of the invention is the method of selectivelyinhibiting a first voltage-gated sodium channel over a secondvoltage-gated sodium channel in a mammal, wherein the method comprisesadministering to the mammal an inhibitory amount of a compound offormula (I), or an embodiment of a compound of formula (I).

Another embodiment of the invention is the method of selectivelyinhibiting NaV1.7 in a mammal or a mammalian cell as compared to NaV1.5,wherein the method comprises administering to the mammal in need thereofan inhibitory amount of a compound of formula (I) or an embodiment of anembodiment thereof.

For each of the above embodiments described related to treating diseasesand conditions in a mammal, the present invention also contemplatesrelatedly a compound of formula I or an embodiment thereof for the useas a medicament in the treatment of such diseases and conditions.

For each of the above embodiments described related to treating diseasesand conditions in a mammal, the present invention also contemplatesrelatedly the use of a compound of formula I or an embodiment thereoffor the manufacture of a medicament for the treatment of such diseasesand conditions.

Another embodiment of the invention is a method of using the compoundsof formula (I) as standards or controls in in vitro or in vivo assays indetermining the efficacy of test compounds in modulatingvoltage-dependent sodium channels.

In another embodiment of the invention, the compounds of formula (I) areisotopically-labeled by having one or more atoms therein replaced by anatom having a different atomic mass or mass number. Suchisotopically-labeled (i.e., radiolabelled) compounds of formula (I) areconsidered to be within the scope of this invention. Examples ofisotopes that can be incorporated into the compounds of formula (I)include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, chlorine, and iodine, such as, but not limited to, ²H,³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl,¹²³I, and ¹²⁵I, respectively. These isotopically-labeled compounds wouldbe useful to help determine or measure the effectiveness of thecompounds, by characterizing, for example, the site or mode of action onthe sodium channels, or binding affinity to pharmacologically importantsite of action on the sodium channels, particularly NaV1.7. Certainisotopically-labeled compounds of formula (I), for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

Testing Compounds

The assessment of the compounds of the invention in mediating,especially inhibiting, the sodium channel ion flux can be determinedusing the assays described hereinbelow. Alternatively, the assessment ofthe compounds in treating conditions and diseases in humans may beestablished in industry standard animal models for demonstrating theefficacy of compounds in treating pain. Animal models of humanneuropathic pain conditions have been developed that result inreproducible sensory deficits (allodynia, hyperalgesia, and spontaneouspain) over a sustained period of time that can be evaluated by sensorytesting. By establishing the degree of mechanical, chemical, andtemperature induced allodynia and hyperalgesia present, severalphysiopathological conditions observed in humans can be modeled allowingthe evaluation of pharmacotherapies.

In rat models of peripheral nerve injury, ectopic activity in theinjured nerve corresponds to the behavioural signs of pain. In thesemodels, intravenous application of the sodium channel blocker and localanesthetic lidocaine can suppress the ectopic activity and reverse thetactile allodynia at concentrations that do not affect general behaviourand motor function (Mao, J. and Chen, L. L, Pain (2000), 87:7-17).Allometric scaling of the doses effective in these rat models,translates into doses similar to those shown to be efficacious in humans(Tanelian, D. L. and Brose, W. G., Anesthesiology (1991),74(5):949-951). Furthermore, Lidoderm®, lidocaine applied in the form ofa dermal patch, is currently an FDA approved treatment for post-herpeticneuralgia (Devers, A. and Glaler, B. S., Clin. J. Pain (2000),16(3):205-8).

The present invention readily affords many different means foridentification of sodium channel modulating agents that are useful astherapeutic agents. Identification of modulators of sodium channel canbe assessed using a variety of in vitro and in vivo assays, e.g.,measuring current, measuring membrane potential, measuring ion flux,(e.g., sodium or guanidinium), measuring sodium concentration, measuringsecond messengers and transcription levels, and using e.g.,voltage-sensitive dyes, radioactive tracers, and patch-clampelectrophysiology.

One such-protocol involves the screening of chemical agents for abilityto modulate the activity of a sodium channel thereby identifying it as amodulating agent.

A typical assay described in Bean et al., J. General Physiology (1983),83:613-642, and Leuwer, M., et al., Br. J. Pharmacol (2004),141(1):47-54, uses patch-clamp techniques to study the behaviour ofchannels. Such techniques are known to those skilled in the art, and maybe developed, using current technologies, into low or medium throughputassays for evaluating compounds for their ability to modulate sodiumchannel behaviour.

Throughput of test compounds is an important consideration in the choiceof screening assay to be used. In some strategies, where hundreds ofthousands of compounds are to be tested, it is not desirable to use lowthroughput means. In other cases, however, low throughput issatisfactory to identify important differences between a limited numberof compounds. Often it will be necessary to combine assay types toidentify specific sodium channel modulating compounds.

Electrophysiological assays using patch clamp techniques is accepted asa gold standard for detailed characterization of sodium channel compoundinteractions, and as described in Bean et al., op. cit. and Leuwer, M.,et al., op. cit. There is a manual low-throughput screening (LTS) methodwhich can compare 2-10 compounds per day; a recently developed systemfor automated medium-throughput screening (MTS) at 20-50 patches (i.e.compounds) per day; and a technology from Molecular Devices Corporation(Sunnyvale, Calif.) which permits automated high-throughput screening(HTS) at 1000-3000 patches (i.e. compounds) per day.

One automated patch-clamp system utilizes planar electrode technology toaccelerate the rate of drug discovery. Planar electrodes are capable ofachieving high-resistance, cells-attached seals followed by stable,low-noise whole-cell recordings that are comparable to conventionalrecordings. A suitable instrument is the PatchXpress 7000A (AxonInstruments Inc, Union City, Calif.). A variety of cell lines andculture techniques, which include adherent cells as well as cellsgrowing spontaneously in suspension are ranked for seal success rate andstability. Immortalized cells (e.g. HEK and CHO) stably expressing highlevels of the relevant sodium ion channel can be adapted intohigh-density suspension cultures.

Other assays can be selected which allow the investigator to identifycompounds which block specific states of the channel, such as the openstate, closed state or the resting state, or which block transition fromopen to closed, closed to resting or resting to open. Those skilled inthe art are generally familiar with such assays.

Binding assays are also available. Designs include traditionalradioactive filter based binding assays or the confocal basedfluorescent system available from Evotec OAI group of companies(Hamburg, Germany), both of which are HTS.

Radioactive flux assays can also be used. In this assay, channels arestimulated to open with veratridine or aconitine and held in astabilized open state with a toxin, and channel blockers are identifiedby their ability to prevent ion influx. The assay can use radioactive22[Na] and 14[α] guanidinium ions as tracers. FlashPlate & Cytostar-Tplates in living cells avoids separation steps and are suitable for HTS.Scintillation plate technology has also advanced this method to HTSsuitability. Because of the functional aspects of the assay, theinformation content is reasonably good.

Yet another format measures the redistribution of membrane potentialusing the FLIPR system membrane potential kit (HTS) available fromMolecular Dynamics (a division of Amersham Biosciences, Piscataway,N.J.). This method is limited to slow membrane potential changes. Someproblems may result from the fluorescent background of compounds. Testcompounds may also directly influence the fluidity of the cell membraneand lead to an increase in intracellular dye concentrations. Still,because of the functional aspects of the assay, the information contentis reasonably good.

Sodium dyes can be used to measure the rate or amount of sodium ioninflux through a channel. This type of assay provides a very highinformation content regarding potential channel blockers. The assay isfunctional and would measure Na+ influx directly. CoroNa Red, SBFIand/or sodium green (Molecular Probes, Inc. Eugene Oreg.) can be used tomeasure Na influx; all are Na responsive dyes. They can be used incombination with the FLIPR instrument. The use of these dyes in a screenhas not been previously described in the literature. Calcium dyes mayalso have potential in this format.

In another assay, FRET based voltage sensors are used to measure theability of a test compound to directly block Na influx. Commerciallyavailable HTS systems include the VIPR™ II FRET system (LifeTechnologies, or Aurora Biosciences Corporation, San Diego, Calif., adivision of Vertex Pharmaceuticals, Inc.) which may be used inconjunction with FRET dyes, also available from Aurora Biosciences. Thisassay measures sub-second responses to voltage changes. There is norequirement for a modifier of channel function. The assay measuresdepolarization and hyperpolarizations, and provides ratiometric outputsfor quantification. A somewhat less expensive MTS version of this assayemploys the FLEXstation™ (Molecular Devices Corporation) in conjunctionwith FRET dyes from Aurora Biosciences. Other methods of testing thecompounds disclosed herein are also readily known and available to thoseskilled in the art.

Modulating agents so identified are then tested in a variety of in vivomodels so as to determine if they alleviate pain, especially chronicpain or other conditions such as cancer and pruritus (itch) with minimaladverse events. The assays described below in the Biological AssaysSection are useful in assessing the biological activity of the instantcompounds.

Typically, the efficacy of a compound of the invention is expressed byits IC50 value (“Inhibitory Concentration—50%”), which is the measure ofthe amount of compound required to achieve 50% inhibition of theactivity of the target sodium channel over a specific time period. Forexample, representative compounds of the present invention havedemonstrated IC50's ranging from less than 100 nanomolar to less than 10micromolar in the patch voltage clamp NaV1.7 electrophysiology assaydescribed herein.

In another aspect of the invention, the compounds of the invention canbe used in in vitro or in vivo studies as exemplary agents forcomparative purposes to find other compounds also useful in treatmentof, or protection from, the various diseases disclosed herein.

Another aspect of the invention relates to inhibiting NaV1.1, NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 activity,preferably NaV1.7 activity, in a biological sample or a mammal,preferably a human, which method comprises administering to the mammal,preferably a human, or contacting said biological sample with a compoundof formula (I) or a pharmaceutical composition comprising a compound offormula (I). The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,NaV1.8, or NaV1.9 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumion channels in biological and pathological phenomena; and thecomparative evaluation of new sodium ion channel inhibitors.

The compounds of the invention (or stereoisomers, geometric isomers,tautomers, solvates, metabolites, isotopes, pharmaceutically acceptablesalts, or prodrugs thereof) and/or the pharmaceutical compositionsdescribed herein which comprise a pharmaceutically acceptable excipientand one or more compounds of the invention, can be used in thepreparation of a medicament for the treatment of sodium channel-mediateddisease or condition in a mammal.

D. Combination Therapy

The compounds of the invention may be usefully combined with one or moreother compounds of the invention or one or more other therapeutic agentor as any combination thereof, in the treatment of sodiumchannel-mediated diseases and conditions. For example, a compound of theinvention may be administered simultaneously, sequentially or separatelyin combination with other therapeutic agents, including, but not limitedto:

-   -   opiates analgesics, e.g., morphine, heroin, cocaine,        oxymorphine, levorphanol, levallorphan, oxycodone, codeine,        dihydrocodeine, propoxyphene, nalmefene, fentanyl, hydrocodone,        hydromorphone, meripidine, methadone, nalorphine, naloxone,        naltrexone, buprenorphine, butorphanol, nalbuphine and        pentazocine;    -   non-opiate analgesics, e.g., acetomeniphen, salicylates (e.g.,        aspirin);    -   nonsteroidal antiinflammatory drugs (NSAIDs), e.g., ibuprofen,        naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac,        diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,        flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,        meclofenamic acid, mefenamic acid, meloxicam, nabumetone,        naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin,        phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin and        zomepirac;    -   anticonvulsants, e.g., carbamazepine, oxcarbazepine,        lamotrigine, valproate, topiramate, gabapentin and pregabalin;    -   antidepressants such as tricyclic antidepressants, e.g.,        amitriptyline, clomipramine, despramine, imipramine and        nortriptyline;    -   COX-2 selective inhibitors, e.g., celecoxib, rofecoxib,        parecoxib, valdecoxib, deracoxib, etoricoxib, and lumiracoxib;    -   alpha-adrenergics, e.g., doxazosin, tamsulosin, clonidine,        guanfacine, dexmetatomidine, modafinil, and        4-amino-6,7-dimethoxy-2-(5-methane        sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)        quinazoline;    -   barbiturate sedatives, e.g., amobarbital, aprobarbital,        butabarbital, butabital, mephobarbital, metharbital,        methohexital, pentobarbital, phenobartital, secobarbital,        talbutal, theamylal and thiopental;    -   tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1        antagonist, e.g., (αR′,        9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diaz        ocino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637),        5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl)ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one        (MK-869), aprepitant, lanepitant, dapitant or        3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine        (2S,3S);    -   coal-tar analgesics, in particular paracetamol;    -   serotonin reuptake inhibitors, e.g., paroxetine, sertraline,        norfluoxetine (fluoxetine desmethyl metabolite), metabolite        demethylsertraline, ′3 fluvoxamine, paroxetine, citalopram,        citalopram metabolite desmethylcitalopram, escitalopram,        d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin,        litoxetine, dapoxetine, nefazodone, cericlamine, trazodone and        fluoxetine;    -   noradrenaline (norepinephrine) reuptake inhibitors, e.g.,        maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,        tomoxetine, mianserin, buproprion, buproprion metabolite        hydroxybuproprion, nomifensine and viloxazine (Vivalan®)),        especially a selective noradrenaline reuptake inhibitor such as        reboxetine, in particular (S,S)-reboxetine, and venlafaxine        duloxetine neuroleptics sedative/anxiolytics;    -   dual serotonin-noradrenaline reuptake inhibitors, such as        venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,        clomipramine, clomipramine metabolite desmethylclomipramine,        duloxetine, milnacipran and imipramine;    -   acetylcholinesterase inhibitors such as donepezil;    -   5-HT3 antagonists such as ondansetron;    -   metabotropic glutamate receptor (mGluR) antagonists;    -   local anaesthetic such as mexiletine and lidocaine;    -   corticosteroid such as dexamethasone;    -   antiarrhythimics, e.g., mexiletine and phenyloin;    -   muscarinic antagonists, e.g., tolterodine, propiverine, tropsium        t chloride, darifenacin, solifenacin, temiverine and        ipratropium;    -   cannabinoids;    -   vanilloid receptor agonists (e.g., resinferatoxin) or        antagonists (e.g., capsazepine);    -   sedatives, e.g., glutethimide, meprobamate, methaqualone, and        dichloralphenazone;    -   anxiolytics such as benzodiazepines,    -   antidepressants such as mirtazapine,    -   topical agents (e.g., lidocaine, capsacin and resiniferotoxin);    -   muscle relaxants such as benzodiazepines, baclofen,        carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol and        orphrenadine;    -   anti-histamines or H1 antagonists;    -   NMDA receptor antagonists;    -   5-HT receptor agonists/antagonists;    -   PDEV inhibitors;    -   Tramadol®;    -   cholinergic (nicotinc) analgesics;    -   alpha-2-delta ligands;    -   prostaglandin E2 subtype antagonists;    -   leukotriene B4 antagonists;    -   5-lipoxygenase inhibitors; and    -   5-HT3 antagonists.

Sodium channel-mediated diseases and conditions that may be treatedand/or prevented using such combinations include but not limited to,pain, central and peripherally mediated, acute, chronic, neuropathic aswell as other diseases with associated pain and other central nervousdisorders such as epilepsy, anxiety, depression and bipolar disease; orcardiovascular disorders such as arrhythmias, atrial fibrillation andventricular fibrillation; neuromuscular disorders such as restless legsyndrome and muscle paralysis or tetanus; neuroprotection againststroke, neural trauma and multiple sclerosis; and channelopathies suchas erythromyalgia and familial rectal pain syndrome.

As used herein “combination” refers to any mixture or permutation of oneor more compounds of the invention and one or more other compounds ofthe invention or one or more additional therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include simultaneous orsequentially delivery of a compound of the invention with one or moretherapeutic agents. Unless the context makes clear otherwise,“combination” may include dosage forms of a compound of the inventionwith another therapeutic agent. Unless the context makes clearotherwise, “combination” may include routes of administration of acompound of the invention with another therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include formulations ofa compound of the invention with another therapeutic agent. Dosageforms, routes of administration and pharmaceutical compositions include,but are not limited to, those described herein.

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

EXAMPLES

These examples serve to provide guidance to a skilled artisan to prepareand use the compounds, compositions and methods of the invention. Whileparticular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinventions.

The chemical reactions in the examples described can be readily adaptedto prepare a number of other compounds of the invention, and alternativemethods for preparing the compounds of this invention are deemed to bewithin the scope of this invention. For example, the synthesis ofnon-examplified compounds according to the invention can be successfullyperformed by modifications apparent to those skilled in the art, forexample, by appropriately protecting interferring group, by utilizingother suitable reagents known in the art, for example, by appropriatelyprotecting interferring groups by utilizing other suitable reagentsknown in the art other than those described, and/or by making routinemodifications of reaction conditions.

In the examples below, unless otherwise indicated all temperatures areset forth in degrees Celcius. Commerically available reagents werepurchased from suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge and were used without further purification unlessotherwise indicated. The reactions set forth below were done generallyunder a positive pressure of nitrogen or argon or with a drying tube(unless otherwise stated) in anhydrous solvents, and the reaction flaskswere typically fitted with rubber septa for the introduction ofsubstrates and reagents via syringe. Glassware was oven dried and/orheat dried. ¹H NMR spectra were obtained in deuterated CDCl₃, d₆-DMSO,CH₃OD or d₆-acetone solvent solutions (reported in ppm) using ortrimethylsilane (TMS) or residual non-deuterated solvent peaks as thereference standard. When peak multiplicities are reported, the followingabbreviates are used: (singlet), d (doublet), t (triplet), q (quartet),m (multiplet, br (broadened), dd (doublet of doublets), dt (doublet oftriplets). Coupling constants, when given, ar reported in Hz (Hertz).

All abbreviations used to describe reagents, reaction conditions orequipment are intended to be consistent with the definitions set forthin the “List of standard abbreviates and acronyms”. The chemical namesof discrete compounds of the invention were obtained using the structurenaming feature of ChemDraw naming program.

Certain final compounds were analyzed by LC/MS methods as describedhereinbelow, with UV detector monitoring at 214 nm and 254 nm, and massspectrometry scanning 110-800 amu in ESI+ ionization mode.

LC/MS Method A: column: XBridge C18, 4.6×50 mm, 3.5 um; mobile phase: Awater (10 mM ammonium hydrogen carbonate), B CH₃CN; gradient: 5%-95% Bin 8.0 min; flow rate: 1.2 mL/min; oven temperature 40° C.

LC/MS Method B: column: XBridge C18, 4.6×50 mm, 3.5 um; mobile phase: Awater (0.1% ammonia), B CH₃CN; gradient: 5%-95% B in 8.0 min; flow rate:1.2 mL/min; oven temperature 40° C.

LC/MS Method C: column: XBridge C18, 4.6×50 mm, 3.5 um; mobile phase: Awater (0.1% TFA), B CH₃CN; gradient: 5%-95% B in 8.0 min; flow rate: 1.2mL/min; oven temperature 40° C.

LC/MS Method D: column: Agilent SB C18, 2.1×30 mm, 1.8 m; mobile phase:A water (0.05% TFA), B CH₃CN (0.05% TFA); gradient: 3% B (0.3 min),followed by 3-95% B (6.5 min), 95% B (1.5 min); flow rate: 0.4 mL/min;oven temperature 25° C.

Abbreviations used herein are as follows:

-   EtOAc Ethyl acetate-   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene-   DCE Dichloroethane-   DCM DCM-   DIPEA Diisopropylethylamine-   DMAP 4-dimethylaminopryidine-   DME Ethyleneglycol dimethyl ether-   DMF N,N-Dimethylformamide-   DMSO Dimethylsulfoxide-   EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-   HBTU N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uranium    hexafluorophosphate-   HCl Hydrochloric acid-   HPLC High Pressure Liquid Chromatography-   IMS Industrial methylated spirits-   LCMS Liquid Chromatography Mass Spectrometry-   MeCN Acetonitrile-   MeOH Methanol-   NMP N-methyl-2-pyrrolidone-   RPHPLC Reverse phase high pressure liquid chromatography-   RT Retention time-   SCX-2 Isolute® silica-based sorbent with a chemically bonded    propylsulfonic acid functional group-   NH₂ cartridge Isolute® silica-based sorbent with a chemically bonded    Aminopropyl functional group-   THF Tetrahydrofuran

Example 1 Synthesis of4-(2-cyclopropylethoxy)-2,5-difluoro-N-(methylsulfonyl)benzamide

To a mixture of 2-cyclopropylethanol (0.172 g, 2.0 mmol) in anhydrousN,N-dimethylformamide (20 mL) was added sodium hydride (60% in mineraloil, 0.20 g, 5.0 mmol) at room temperature. The resulting mixture wasstirred at 45° C. for 30 min and then cooled to room temperature.2,4,5-Trifluoro-N-(methylsulfonyl)benzamide (WO 2012007883 A1) (0.51 g,2.2 mmol) was added and the reaction mixture was stirred at roomtemperature for 16 h. The mixture was cooled to 0° C. and quenched withhydrochloride acid (1N, 30 mL) followed by extraction with ethyl acetate(100 mL). The organic layer was washed with water (30 mL), dried overanhydrous sodium sulfate, and filtered. The filtrate was concentrated invacuo, the crude product was purified by silica gel columnchromatography using 10-60% ethyl acetate (containing 2% acetic acid) inhexanes as an eluent to afford the title compound as a white solid (0.12g, 19%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.06 (brs, 1H), 7.58 (dd, J=6.9 Hz& 11.4 Hz, 1H), 7.30 (dd, J=6.9 Hz & 12.1 Hz, 1H), 4.19 (t, J=6.6 Hz,2H), 3.35 (s, 3H), 1.69-1.62 (m, 2H), 0.88-0.74 (m, 1H), 0.47-0.41 (m,2H), 0.16-0.11 (m, 2H); MS (ES−) m/z 318.1 (M−1).

Example 2 Synthesis of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 1 and making variationsas required to replace 2-cyclopropylethanol with adamantan-1-ylmethanoland 2,4,5-trifluoro-N-(methylsulfonyl)benzamide with5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (WO 2012007883 A1),the title compound was obtained as a colorless solid (0.20 g, 8%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.10 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.23 (d,J=12.5 Hz, 1H), 3.72 (s, 2H), 3.35 (s, 3H), 1.99 (br s, 3H), 1.75-1.64(m, 12H); ¹³C NMR (75 MHz, DMSO-d₆) δ 162.3 (d, J=2.0 Hz), 159.8 (d,J_(C-F)=255 Hz), 158.3 (d, J_(C-F)=11 Hz), 130.6 (d, J_(C-F)=4 Hz),116.8 (d, J_(C-F)=3 Hz), 113.6 (d, J_(C-F)=14 Hz), 102.7 (d, J_(C-F)=28Hz), 79.1, 41.2, 38.5, 36.4, 33.4, 27.3; MS (ES+) m/z 415.6, 417.6(M+1).

Example 3 Synthesis of4-(adamantan-2-yloxy)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 1 and making variationsas required to replace 2-cyclopropylethanol with adamantan-2-ol and2,4,5-trifluoro-N-(methylsulfonyl)benzamide with5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide, the title compoundwas obtained as a colorless solid (0.055 g, 4%): ¹H NMR (300 MHz,DMSO-d₆) δ 12.07 (s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.33 (d, J=12.6 Hz,1H), 4.82 (br s, 1H), 3.34 (s, 3H), 2.08-2.03 (m, 4H), 1.84 (br s, 6H),1.71 (br s, 2H), 1.55-1.51 (m, 2H); MS (ES−) m/z 400.1, 402.1 (M−1).

Example 4 Synthesis of5-chloro-4-(((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 1 and making variationsas required to replace 2-cyclopropylethanol with((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]-heptan-2-yl)methanol and2,4,5-trifluoro-N-(methylsulfonyl)benzamide with5-chloro-2,4-difluoro-N-(methylsulfonyl)-benzamide, the title compoundwas obtained as a colorless solid (0.03 g, 2%): ¹H NMR (300 MHz,DMSO-d₆) δ 12.10 (s, 1H), 7.76 (d, J=7.4 Hz, 1H), 7.25 (d, J=12.5 Hz,1H), 3.96 (d, J=6.8 Hz, 2H), 3.35 (s, 3H), 2.47-2.37 (m, 1H), 2.10-2.03(m, 1H), 1.94-1.65 (m, 5H), 1.48-1.37 (m, 2H), 1.12 (s, 3H), 0.85 (s,3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 162.3 (d, J=2 Hz), 159.8 (d,J_(C-F)=255 Hz), 158.1 (d, J_(C-F)=11 Hz), 130.7 (d, J_(C-F)=3 Hz),116.6 (d, J_(C-F)=3 Hz), 113.7 (d, J_(C-F)=14 Hz), 102.5 (d, J_(C-F)=28Hz), 73.1, 41.9, 41.2, 40.1, 38.8, 34.1, 26.5, 23.5, 23.1, 20.0, 17.4;MS (ES−) m/z 402.1, 404.1 (M−1).

Example 5 Synthesis of4-(2-(adamantan-1-yl)ethoxy)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 1 and making variationsas required to replace 2-cyclopropylethanol with2-(adamantan-1-yl)ethanol and2,4,5-trifluoro-N-(methylsulfonyl)benzamide with5-chloro-2,4-difluoro-N-(methylsulfonyl)-benzamide, the title compoundwas obtained as a colorless solid (0.04 g, 5%): ¹H NMR (300 MHz,DMSO-d₆) δ 12.06 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.6 Hz,1H), 4.15 (t, J=6.9 Hz, 2H), 3.31 (s, 3H), 1.89 (br s, 3H), 1.66-1.51(m, 14H); ¹³C NMR (75 MHz, DMSO-d₆) δ 162.3 (d, J_(C-F)=2 Hz), 159.9 (d,J_(C-F)=254 Hz), 158.1 (d, J_(C-F)=12 Hz), 130.7 (d, J_(C-F)=4 Hz),116.5 (d, J_(C-F)=3 Hz), 113.6 (d, J_(C-F)=14 Hz), 102.5 (d, J_(C-F)=28Hz), 66.1, 42.1, 41.8, 41.2, 36.4, 31.3, 27.9; MS (ES−) m/z 428.1, 430.1(M−1).

Example 6 Synthesis of4-((adamantan-1-ylmethoxy)-2,5-difluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 1 and making variationsas required to replace 2-cyclopropylethanol with adamantan-1-ylmethanol,the title compound was obtained as a colorless solid (0.145 g, 36%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.01 (s, 1H), 7.53 (dd, J=6.8, 11.3 Hz, 1H),7.23 (dd, J=6.8, 12.3 Hz, 1H), 3.68 (s, 2H), 3.31 (s, 3H), 1.95 (s, 3H),1.71-1.58 (m, 12H); MS (ES−) m/z 398.1 (M−1).

Example 7 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)oxy)benzamide

Following the procedure as described in Example 1 and making variationsas required to replace 2-cyclopropylethanol with(1R,2R,3R,5S)-2,6,6-trimethylbicyclo-[3.1.1]heptan-3-ol and2,4,5-trifluoro-N-(methylsulfonyl)benzamide with5-chloro-2,4-difluoro-N-(methylsulfonyl)-benzamide, the title compoundwas obtained as a colorless solid (0.06 g, 5%): ¹H NMR (300 MHz,DMSO-d₆) δ 12.05 (s, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.33 (d, J_(C-F)=12.6Hz, 1H), 4.79-4.74 (m, 1H), 3.31 (s, 3H), 2.71-2.64 (m, 1H), 2.37-2.26(m, 2H), 1.91-1.80 (m, 2H), 1.59-1.52 (m, 1H), 1.19 (s, 3H), 1.10-1.06(m, 4H), 0.95 (s, 3H); MS (ES−) m/z 402.1, 404.1 (M−1).

Example 8 Synthesis of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

To a mixture of adamantan-1-ylmethanol (1.00 g, 6.0 mmol) in anhydrousdimethyl sulfoxide (40 mL) was added potassium t-butoxide (1.68 g, 15.0mmol) at room temperature. The resulting mixture was stirred at roomtemperature for 30 min followed by the addition of5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (1.62 g, 6.0 mmol).The reaction mixture was stirred at room temperature for 16 h. Themixture was cooled to 0° C. and quenched with hydrochloride acid (1N, 30mL) followed by extraction with ethyl acetate (200 mL). The organiclayer was washed with water (2×40 mL), dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated in vacuo, the crudeproduct was purified by silica gel column chromatography using 10-60%ethyl acetate (containing 0.2% acetic acid) in hexanes as an eluent toafford the title compound as a white solid (1.17 g, 46%): ¹H NMR (300MHz, DMSO-d₆) δ 12.10 (s, 1H), 7.77 (d, J=7.5 Hz 1H), 7.23 (d, J=12.5Hz, 1H), 3.72 (s, 2H), 3.35 (s, 3H), 1.99 (br s, 3H), 1.75-1.64 (m,12H); ¹³C NMR (75 MHz, DMSO-d₆) δ 162.3 (d, J=2.2 Hz), 159.8 (d,J_(C-F)=255 Hz), 158.3 (d, J_(C-F)=11 Hz), 130.6 (d, J_(C-F)=4 Hz),116.8 (d, J_(C-F)=3 Hz), 113.6 (d, J_(C-F)=14 Hz), 102.7 (d, J_(C-F)=28Hz), 79.1, 41.2, 38.5, 36.4, 33.4, 27.3; MS (ES−) m/z 414.1, 416.1(M−1).

Example 9 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)oxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ol, the titlecompound was obtained as a colorless solid (0.27 g, 45%): ¹H NMR (300MHz, DMSO-d₆) δ 12.07 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.6Hz, 1H), 4.81-4.78 (m, 1H), 3.35 (s, 3H), 2.75-2.67 (m, 1H), 2.40-2.30(m, 2H), 1.94-1.85 (m, 2H), 1.61-1.56 (m, 1H), 1.22 (s, 3H), 1.14-1.09(m, 4H), 0.98 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 162.3 (d, J=2 Hz),159.8 (d, J_(C-F)=254 Hz), 157.3 (d, J_(C-F)=11 Hz), 130.8 (d, J_(C-F)=3Hz), 117.5 (d, J_(C-F)=3 Hz), 113.7 (d, J_(C-F)=14 Hz), 104.0 (d,J_(C-F)=27 Hz), 78.6, 46.5, 43.7, 41.2, 40.5, 37.7, 34.6, 32.1, 27.1,23.5, 20.5; MS (ES−) m/z 402.1, 404.1 (M−1).

Example 10 Synthesis of5-chloro-4-(2-cyclopropylethoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with 2-cyclopropylethanol,the title compound was obtained as a colorless solid (0.26 g, 52%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.13 (s, 1H), 7.78 (d, J=7.5 Hz 1H), 7.26 (d,J=12.5 Hz, 1H), 4.20 (t, J=6.3 Hz, 2H), 3.35 (s, 3H), 1.70-1.63 (m, 2H),0.87-0.79 (m, 1H), 0.47-0.41 (m, 2H), 0.17-0.12 (m, 2H); ¹³C NMR (75MHz, DMSO-d₆) F 162.3 (d, J=2 Hz), 159.9 (d, J_(C-F)=254 Hz), 158.1 (d,J_(C-F)=11 Hz), 130.8 (d, J_(C-F)=3 Hz), 116.6 (d, J_(C-F)=3 Hz), 113.7(d, J_(C-F)=14 Hz), 102.5 (d, J_(C-F)=27 Hz), 70.3, 41.7, 33.5, 8.0,4.5; MS (ES−) m/z 334.1, 336.1 (M−1).

Example 11 Synthesis of5-chloro-2-fluoro-4-((3-fluoroadamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with3-fluoroadamantan-1-ylmethanol, the title compound was obtained as acolorless solid (0.37 g, 58%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.12 (s,1H), 7.78 (d, J=7.5 Hz, 1H), 7.24 (d, J=12.4 Hz, 1H), 3.85 (s, 2H), 3.35(s, 3H), 2.30 (s, 2H), 1.82-1.76 (m, 6H), 1.61-1.52 (m, 6H); ¹³C NMR (75MHz, DMSO-d₆) δ 162.3 (d, J=2 Hz), 159.8 (d, J_(C-F)=254 Hz), 158.1 (d,J_(C-F)=11 Hz), 130.7 (d, J_(C-F)=3 Hz), 116.8 (d, J_(C-F)=3 Hz), 113.8(d, J_(C-F)=14 Hz), 102.6 (d, J_(C-F)=28 Hz), 92.5 (d, J_(C-F)=183 Hz),77.6 (d, J_(C-F)=1 Hz), 43.7 (d, J_(C-F)=18 Hz), 41.8 (d, J_(C-F)=17Hz), 41.2, 38.3 (d, J_(C-F)=10 Hz), 37.0 (d, J_(C-F)=2 Hz), 34.6 (d,J_(C-F)=2 Hz), 30.3 (d, J_(C-F)=10 Hz); MS (ES−) m/z 432.1, 434.1 (M−1).

Example 12 Synthesis of4-(adamantan-1-ylmethoxy)-3-chloro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 3-chloro-4-fluoro-N-(methylsulfonyl)benzamide, the title compoundwas obtained as a colorless solid (0.34 g, 52%): ¹H NMR (300 MHz,DMSO-d₆) δ 12.07 (s, 1H), 8.04-7.94 (m, 2H), 7.25 (d, J=8.5 Hz, 1H),3.72 (s, 2H), 3.36 (s, 3H), 1.99 (br, 3H), 1.71-1.66 (m, 12H); MS (ES−)m/z 396.1, 398.1 (M−1).

Example 13 Synthesis of4-(2-(adamantan-1-yl)ethoxy)-3-chloro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with2-(adamantan-1-yl)ethanol and5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with3-chloro-4-fluoro-N-(methylsulfonyl)benzamide, the title compound wasobtained as a colorless solid (0.43 g, 71%): ¹H NMR (300 MHz, DMSO-d₆) δ12.06 (s, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.93 (dd, J=8.7 Hz, 2.2 Hz, 1H),7.31 (d, J=8.7 Hz, 1H), 4.20 (t, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.93 (brs, 3H), 1.70-1.55 (m, 14H); MS (ES+) m/z 411.8, 413.8 (M+1).

Example 14 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with[(1S)-endo]-(−)-borneol, the title compound was obtained as a colorlesssolid (0.18 g, 24%): ¹H NMR (300 MHz, CDCl₃) δ 8.68 (s, 1H), 8.15-8.04(m, 1H), 6.63-6.50 (m, 1H), 4.44-4.32 (m, 1H), 3.43 (s, 3H), 2.50-2.23(m, 2H), 1.88-1.74 (m, 2H), 1.49-1.36 (m, 1H), 1.35-1.21 (m, 1H),1.15-1.05 (m, 1H), 1.01-0.89 (m, 9H); MS (ES−) m/z 402.1 (M−1), 404.1(M−1).

Example 15 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-((exo-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with is isoborneol, thetitle compound was obtained as a colorless solid (0.18 g, 24%): ¹H NMR(300 MHz, CDCl₃) δ 10.04 (s, 1H), 8.33-8.20 (m, 1H), 6.87-6.74 (m, 1H),4.28-4.06 (m, 1H), 3.38 (s, 3H), 2.06-1.62 (m, 5H), 1.29-1.06 (m, 8H),0.94 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 160.4 (d, J_(C-F)=248.69 Hz),160.3 (d, J_(C-F)=3.43 Hz), 159.0 (d, J_(C-F)=12.21 Hz), 132.7 (d,J_(C-F)=3.20 Hz), 120.8 (d, J_(C-F)=2.62 Hz), 109.9 (d, J_(C-F)=11.91Hz), 101.3 (d, J_(C-F)=30.39 Hz), 87.1, 49.7, 47.2, 45.3, 42.0, 39.0,33.8, 27.2, 20.2, 20.1, 11.7; MS (ES−) m/z 402.1 (M−1), 404.1 (M−1).

Example 16 Synthesis of5-chloro-4-((−3,5-dimethyladamantan-1-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with is3,5-dimethyl-1-adamantanemethanol, the title compound was obtained as acolorless solid (0.37 g, 41%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (s,1H), 7.76 (d, J=7.2 Hz 1H), 7.21 (d, J=12.0 Hz, 1H), 3.75 (s, 2H), 3.35(s, 3H), 1.47 (s, 1H), 1.33-1.07 (m, 12H), 0.81 (s, 6H); ¹³C NMR (75MHz, DMSO-d₆) δ 162.2 (d, J=1.8 Hz), 160.3 (d, ¹J_(C-F)=255.7 Hz), 158.8(d, J_(C-F)=11.1 Hz), 131.1 (d, J_(C-F)=3.1 Hz), 117.3 (d, J_(C-F)=2.9Hz), 114.0 (d, J_(C-F)=13.7 Hz), 102.9 (d, ²J_(C-F)=27.5 Hz), 79.1,51.1, 45.4, 43.2, 41.7, 37.7, 35.7, 31.0, 30.9, 29.1; MS (ES−) m/z442.1, 444.1 (M−1).

Example 17 Synthesis of5-chloro-2-fluoro-4-((3-hydroxyadamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with3-(hydroxymethyl)-1-adamantol, the title compound was obtained as acolorless solid (0.25 g, 29%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (s,1H), 7.76 (d, J=6.6 Hz, 1H), 7.23 (d, J=12.3 Hz, 1H), 4.36 (br s, 1H),3.78 (s, 2H), 3.35 (s, 3H), 2.14 (br s, 2H), 1.68-1.39 (m, 12H); MS(ES−) m/z: 430.1, 432.1 (M−1).

Example 18 Synthesis of5-chloro-2-fluoro-4-((3-methoxyadamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with 3-methoxyadamantan-1-ylmethanol, the title compound was obtained as a colorlesssolid (0.28 g, 49%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (s, 1H), 7.77 (d,J=7.5 Hz, 1H), 7.23 (d, J=12.4 Hz, 1H), 3.81 (s, 2H), 3.35 (s, 3H), 3.12(s, 3H), 2.21 (s, 2H), 1.70-1.55 (m, 12H); MS (ES+) m/z 414.0, 416.0(M−OCH₃).

Example 19 Synthesis of4-(1-(adamantan-1-yl)ethoxy)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with1-(adamantan-1-yl)ethanol, the title compound was obtained as acolorless solid (0.22 g, 44%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.04 (s,1H), 7.77-7.74 (m, 1H), 7.30 (d, J=12.7 Hz, 1H), 4.24 (q, J=6.2 Hz, 1H),3.34 (s, 3H), 1.97 (brs, 3H), 1.72-1.56 (m, 12H), 1.16 (d, 6.2 Hz, 3H);MS (ES−) m/z 428.1, 430.1 (M−1).

Example 20 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-((4-pentylbicyclo-[2.2.2]octan-1-yl)methoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with(4-pentylbicyclo[2.2.2]-octan-1-yl)methanol (Jpn. Kokai Tokkyo Koho,2010083938, 15 Apr. 2010), the title compound was obtained as acolorless solid (0.17 g, 49%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (s,1H), 7.76 (d, J=7.5 Hz, 1H), 7.21 (d, J=12.4 Hz, 1H), 3.76 (s, 2H), 3.35(s, 3H), 1.51-1.06 (m, 20H), 0.85 (t, J=6.9 Hz, 3H); MS (ES−) m/z 458.2,460.1 (M−1).

Example 21 Synthesis of5-chloro-4-(cyclohexylmethoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with cyclohexylmethanol,the title compound was obtained as a colorless solid (0.091 g, 25%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.04 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.21 (d,J=12.6 Hz, 1H), 3.93 (d, J=5.9 Hz, 2H), 3.31 (s, 3H), 1.79-1.60 (m, 6H),1.29-0.97 (m, 5H); MS (ES−) m/z 362.1, 364.1 (M−1).

Example 22 Synthesis of5-chloro-4-(2-cyclopentylethoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with 2-cyclopentylethanol,the title compound was obtained as a colorless solid (0.107 g, 29%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.06 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.22 (d,J=12.5 Hz, 1H), 4.12 (t, J=6.5 Hz, 2H), 3.31 (s, 3H), 1.95-1.83 (m, 1H),1.80-1.71 (m, 4H), 1.59-1.42 (m, 4H), 1.18-1.07 (m, 2H); MS (ES−) m/z362.1, 364.1 (M−1).

Example 23 Synthesis of5-chloro-4-(2-cyclohexylethoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with 2-cyclohexylethanol,the title compound was obtained as a colorless solid (0.05 g, 14%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.05 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.26 (d,J=12.4 Hz, 1H), 4.17 (t, J=6.6 Hz, 2H), 3.29 (s, 3H), 1.76-1.41 (m, 8H),1.27-0.90 (m, 5H); MS (ES−) m/z 376.1, 378.1 (M−1).

Example 24/25 Synthesis of5-chloro-4-(((1R,2s,3S,5s,7s)-5-chloroadamantan-2-yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamideand5-chloro-4-(((1R,2r,3S,5s,7s)-5-chloroadamantan-2-yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with5-chloroadamantan-2-ol (J. Am. Chem. Soc. 1986, 108, 1598), the crudeproduct was purified by silica gel column chromatography using 10-60%ethyl acetate (containing 0.2% acetic acid) in hexanes as an eluent toprovide pure separated diastereomers of5-chloro-4-(((1R,2s,3S,5s,7s)-5-chloroadamantan-2-yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamideand5-chloro-4-(((1R,2r,3S,5s,7s)-5-chloroadamantan-2-yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide.Data for first eluting diasteromeomer: a colorless solid (0.22 g, 19%),(Example 24): ¹H NMR (300 MHz, DMSO-d₆) δ 12.05 (s, 1H), 7.75 (d, J=7.5Hz, 1H), 7.36 (d, J=12.6 Hz, 1H), 4.17 (m, 1H), 3.31 (s, 3H), 2.29-2.10(m, 9H), 1.93 (d, J=12.5 Hz, 2H), 1.47 (d, J=12.5 Hz, 2H); MS (ES−) m/z434.0, 436.0, (M−1). Data for the second eluting diasteromer was alsoobtained as a colorless solid (0.15 g, 12%): ¹H NMR (300 MHz, DMSO-d₆) δ12.07 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.36 (d, J=12.6 Hz, 1H), 4.71 (m,1H), 3.31 (s, 3H), 2.37-2.28 (m, 4H), 2.06 (brs, 3H), 1.97-1.93 (m, 2H),1.74 (brs, 4H); MS (ES−) m/z 434.1, 436.1, (M−1).

Example 26 Synthesis of5-chloro-4-(2-cycloheptylethoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with cycloheptylmethanol,the title compound was obtained as a colorless solid (0.12 g, 32%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.06 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.21 (d,J=12.5 Hz, 1H), 3.91 (d, J=6.5 Hz, 2H), 3.31 (s, 3H), 1.98-1.21 (m,13H); MS (ES−) m/z 376.1, 378.1 (M−1).

Example 27 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with (+)-Borneol, thetitle compound was obtained as a colorless solid (0.25 g, 33%): ¹H NMR(300 MHz, CDCl₃) δ 8.68 (s, 1H), 8.13-8.06 (m, 1H), 6.64-6.47 (m, 1H),4.46-4.30 (m, 1H), 3.43 (s, 3H), 2.52-2.21 (m, 2H), 1.89-1.70 (m, 2H),1.49-1.19 (m, 2H), 1.16-1.05 (m, 1H), 1.03-0.79 (m, 9H); MS (ES−) m/z402.1 (M−1), 404.1 (M−1).

Example 28 Synthesis of4-(adamantan-1-ylmethoxy)-5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide (asprepared in Example 31), the title compound was obtained as a colorlesssolid (0.25 g, 38%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.77 (s, 1H), 7.72 (d,J=7.45 Hz 1H), 7.22 (d, J=12.3 Hz, 1H), 3.72 (s, 2H), 2.87 (s, 6H), 1.99(br, 3H), 1.75-1.64 (m, 12H); MS (ES−) m/z 443.1, 445.1 (M−1).

Example 29 Synthesis of4-(adamantan-2-yloxy)-5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with adamantan-2-ol and5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide (as prepared inExample 31), the title compound was obtained as a colorless solid (0.21g, 38%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.73 (s, 1H), 7.74 (d, J=7.5 Hz,1H), 7.33 (d, J=12.5 Hz, 1H), 4.81 (s, 1H), 2.87 (s, 6H), 2.08-2.03 (m,4H), 1.84-1.71 (m, 8H), 1.54-1.50 (m, 2H); MS (ES−) m/z 429.2, 431.2(M−1).

Example 30 Synthesis of5-chloro-4-(((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-methoxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol and5-chloro-2,4-difluoro-N-(methylsulfonyl)-benzamide with5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide (as prepared inExample 31), the title compound was obtained as a colorless solid (0.25g, 45%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.76 (s, 1H), 7.72 (d, J=7.5 Hz,1H), 7.24 (d, J=12.3 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 2.87 (s, 6H),2.50-2.40 (m, 1H), 2.10-1.65 (m, 6H), 1.48-1.37 (m, 2H), 1.21 (s, 3H),0.85 (s, 3H); MS (ES−) m/z 431.2, 433.2 (M−1).

Example 31 Synthesis of5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide

To a mixture of 5-chloro-2,4-difluorobenzoic acid (3.48 g, 18.1 mmol) inanhydrous dichloromethane (100 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.20 g,27.1 mmol), N,N-dimethylpyridin-4-amine (5.04 g, 41.3 mmol), andN,N-dimethylsulfamide (3.37 g, 27.1 mmol) at room temperature. Theresulting mixture was stirred at room temperature for 24 h. The mixturewas then cooled to 0° C. and quenched with hydrochloride acid (1N, 100mL) followed by extraction with dichloromethane (2×200 mL). The organiclayer was washed with ammonium chloride solution (3×30 mL), dried overanhydrous sodium sulfate, and filtered. The filtrate was concentrated invacuo and the crude product was crystallized from ethyl acetate andhexanes to afford the title compound as a white solid (1.20 g, 22%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.05 (s, 1H), 7.98-7.93 (m, 1H), 7.74-7.68 (m,1H), 2.89 (s, 6H); MS (ES−) m/z 297.1, 299.1 (M−1).

Example 32 Synthesis of4-((-adamantan-1-ylmethyl)amino)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

A stirred mixture of 1-(aminomethyl)adamantane (0.31 g, 1.85 mmol),5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (0.5 g, 1.85 mmol) andpotassium carbonate (0.64 g, 4.63 mmol) in N,N-dimethylformamide (18 mL)and tetrahydrofuran (10 mL) was heated at 65° C. for 48 h. The reactionmixture was cooled to room temperature and filtered. The filtrate wasdiluted with saturated aqueous ammonium chloride (50 mL) and ethylacetate (100 mL). The layers were separated and the aqueous layer wasextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with water (100 mL), brine (100 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography, eluting with a 0 to 10% gradient ofmethanol in dichloromethane to afford the title compound as a paleyellow solid (0.064 g, 8%): ¹H NMR (300 MHz, CDCl₃) δ 8.55-8.08 (m, 2H),7.51-7.40 (m, 1H), 6.58-6.43 (m, 1H), 3.44 (s, 3H), 2.84-2.75 (m, 2H),2.02 (br s, 3H), 1.81-1.46 (m, 12H); ¹³C NMR (75 MHz, CDCl₃) δ 166.5,162.5 (d, ¹J_(C-F)=255.0 Hz), 153.1 (d, J_(C-F)=11.8 Hz), 130.9 (d,J_(C-F)=3.2 Hz), 106.8, 106.2 (d, J_(C-F)=19.5 Hz), 99.6 (d,²J_(C-F)=25.3 Hz), 55.7, 42.1, 40.6, 36.9, 33.8, 28.2; MS (ES+) m/z414.8, 416.8 (M+1).

Example 33 Synthesis of6-(Adamantan-1-ylmethoxy)-5-chloro-N-methanesulfonylpyridine-3-carboxamide

Step 1 Preparation of 5,6-dichloronicotinic acid

A mixture of ethyl 5,6-dichloronicotinate (1.0 g, 4.5 mmol) and aqueousNaOH (2 N, 6.75 mL, 13.5 mmol) in a mixed solvents of THF/MeOH/water (50mL, 4/1/1) was stirred at room temperature for 0.5 h. Afterconcentration, the mixture was acidified with 2 N HCl to pH around 2.The resulting mixture was extracted with ether (30 mL×3). The organiclayer was washed with water (50 mL×3), dried over Na₂SO₄, andconcentrated to afford 5,6-dichloronicotinic acid (800 mg, 91% yield) asa white solid. LCMS (ESI) m/z: 192.0 [M+H]⁺.

Step 2 Preparation of 5,6-Dichloro-N-(methylsulfonyl)nicotinamide

A mixture of 5,6-dichloronicotinic acid (800 mg, 4.16 mmol),methanesulfonamide (779 mg, 8.40 mmol), EDCI (1.56 g, 8.20 mmol), andDMAP (1.00 g, 8.20 mmol) in DCM (10 mL) was stirred at room temperaturefor 16 h. The reaction was quenched with water (5 mL) and the resultingmixture was concentrated. The residue was adjusted to pH around 5 by 1MHCl, extracted with DCM (30 mL×3), dried over Na₂SO₄. The organic layerwas concentrated to afford 5,6-dichloro-N-(methylsulfonyl)nicotinamide(700 mg, 62% yield). LCMS (ESI) m/z: 269.0 [M+H]⁺.

Step 36-(Adamantan-1-ylmethoxy)-5-chloro-N-methanesulfonylpyridine-3-carboxamide

To a solution of 5,6-dichloro-N-(methylsulfonyl)nicotinamide (60 mg,0.22 mmol) and 1-(hydroxymethyl) adamantine (182 mg, 1.10 mmol) in DMF(3 mL) at 0° C. was added NaH (60%, 52 mg, 1.3 mmol). The mixture wasthen stirred at 45° C. for 72 h. Sat. NH₄Cl (5 mL) was added to quenchthe reaction and the resulting mixture was extracted with ethyl acetate(5 mL×3). The combined organic layer was dried and concentrated invacuo. The residue was purified by prep-HPLC (Gilson GX 281, Shim-packPRC-ODS 250 mm×20 mm×2, gradient: CH₃CN/10 mm/L NH₄HCO₃, 17 min) toafford 6-(adamantan-1-ylmethoxy)-5-chloro-N-methanesulfonylpyridine-3-carboxamide (20 mg, 22% yield). LCMS (ESI) Method B: RT=4.45min, m/z: 423.0 [M+Na]⁺. ¹H NMR (500 MHz, DMSO-d₆): δ 8.63 (s, 1H), 8.32(s, 1H), 4.02 (s, 2H), 3.27 (s, 3H), 1.98 (s, 3H), 1.73-1.63 (m, 12H).

Example 34 Synthesis of5-Chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethylcyclopropyl)-methoxy)benzamide

Step 1 Preparation of 5-Chloro-2,4-difluoro-N-(methylsulfonyl)benzamide

To a mixture of 5-chloro-2,4-dilfluorobenzoic acid (0.291 g, 1.51 mmol),EDCI (0.438 g, 2.29 mmol), and 4-dimethylaminopyridine (0.420 g, 3.44mmol) in THF (5 mL) was methanesulfonamide (0.222 g, 2.33 mmol). Afterbeing stirred at room temperature for 18 h, the mixture was diluted withDCM (10 mL) and washed with 2 N HCl (15 mL×2). The organic layer wasdried over Na₂SO₄ and concentrated in vacuo to afford5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (0.388 g, 95% yield)as a white solid. LCMS (ESI) m/z: 268 [M−H]⁺. The compound can also beprepared as described in International Patent Application PublicationNumber WO/2012/007883.

Step 2 Preparation of (2,2,3,3-Tetramethylcyclopropyl)methanol

To a stirred solution of 2,2,3,3-tetramethylcyclopetanecarboxylic acid(500 mg, 3.50 mmol) in THF (25 mL) at 0° C. was added 2.0 M boranedimethylsulfide complex in THF (1.8 mL, 3.5 mmol). The mixture was thenwarmed to 50° C. and stirred for 3 h. After cooling to room temperature,methanol (10 mL) was carefully added. The resulting mixture was thenconcentrated and filtered. The filtrate was concentrated to afford(2,2,3,3-tetramethyl-cyclopropyl)methanol (250 mg, 56% yield) as oil. ¹HNMR (500 MHz, CDCl₃): δ 3.67 (d, J=8.0 Hz, 2H), 1.10 (s, 6H), 1.02 (s,6H), 0.54 (t, J=8.0 Hz, 1H).

Step 3 Preparation of5-Chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethylcyclopropyl)-methoxy)benzamide

To a stirred solution of (2,2,3,3-tetramethylcyclopropyl)methanol (80mg, 0.62 mmol) in dry DMF (10 mL) at 0° C. was added NaH (25 mg, 0.62mmol). After being stirred for 30 min,5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (54 mg, 0.21 mmol) wasadded. After being stirred at room temperature for 18 h, the mixture wasdiluted with water (10 mL) and EtOAc (20 mL). The organic layer wasseparated and the aqueous layer was extracted with EtOAc (20 ml×2). Thecombined organic layers was dried over Na₂SO₄ and concentrated. Theresidue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250mm×20 mm×2, gradient: CH₃CN/10 mm/L NH₄HCO₃, 17 min) to afford5-chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethylcyclopropyl)-methoxy)benzamide(20 mg, 25% yield) as a white solid. LCMS (ESI) Method A: RT=5.11 min,m/z: 268 [M-109]⁺. ¹H NMR (500 MHz, DMSO-d₆): δ 7.35 (d, J=9.0 Hz 1H),7.03 (d, J=7.0 Hz, 1H), 6.04 (brs, 1H), 3.99 (d, J=7.5 Hz, 2H), 2.80 (s,3H), 1.06 (s, 6H), 0.99 (s, 6H), 0.65 (t, J=7.5 Hz, 1H); ¹³C NMR (125MHz, MeOH-d₄): δ 159.4 (d, J=3.5 Hz), 133.9 (d, J=2.1 Hz), 114.1, 104.2,103.9, 71.4, 41.7, 32.5, 24.2, 23.7, 17.4.

Example 35 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-(5,6,7,8-tetrahydronaphthalen-2-yloxy)benzamideand5-chloro-4-fluoro-N-(methylsulfonyl)-2-(5,6,7,8-tetrahydronaphthalen-2-yloxy)benzamide

Step 1 Preparation of5-chloro-2-fluoro-N-(methylsulfonyl)-4-(5,6,7,8-tetrahydronaphthalen-2-yloxy)benzamideand5-chloro-4-fluoro-N-(methylsulfonyl)-2-(5,6,7,8-tetrahydronaphthalen-2-yloxy)benzamide

To a solution of 5,6,7,8-tetrahydronaphthalen-2-ol (66 mg, 0.44 mmol) inDMF (3 mL) was added NaH (19 mg, 0.48 mmol). After being stirred at roomtemperature for 0.5 h, 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide(100 mg, 0.37 mmol) was added and the mixture was stirred at roomtemperature for 16 h. Sat. NH₄Cl (10 mL) was added to quench thereaction and the resulting mixture was extracted with ethyl acetate (10mL×3). The combined organic layer was dried over NaSO₄ and concentratedin vacuo. The residue was purified by prep-HPLC (Gilson GX 281,Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH₃CN/10 mm/L NH₄HCO₃, 17min) to afford5-chloro-2-fluoro-N-(methylsulfonyl)-4-(5,6,7,8-tetrahydronaphthalen-2-yloxy)benzamide(44 mg, 30% yield) and5-chloro-4-fluoro-N-(methylsulfonyl)-2-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-benzamide(21 mg, 14% yield).

5-Chloro-2-fluoro-N-(methylsulfonyl)-4-(5,6,7,8-tetrahydronaphthalen-2-yloxy)benzamide.LCMS (ESI) Method B: RT=3.92 min, m/z: 398.1 [M+H]⁺. ¹H NMR (500 MHz,MeOH-d₄): δ 7.57 (d, J=8.5 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.66-6.57(m, 3H), 2.73 (s, 3H), 2.63 (br s, 4H), 1.68 (br s, 4H). ¹³C NMR (125MHz, DMSO-d₆): δ 164.5 (d, J=2.1 Hz), 160.2, 158.2, 155.1 (d, J=8.9 Hz),152.5, 138.9, 133.3, 132.0 (d, J=3.6 Hz), 130.6, 118.8, 118.1 (d, J=3.4Hz), 116.2, 107.0 (d, J=2.8 Hz), 40.7, 28.8, 28.1, 22.6, 22.4.

5-Chloro-4-fluoro-N-(methylsulfonyl)-2-(5,6,7,8-tetrahydronaphthalen-2-yloxy)benzamide.LCMS (ESI) Method B: RT=4.06 min, m/z: 398.0 [M+H]⁺. ¹H NMR (500 MHz,MeOH-d₄): δ 7.90 (d, J=7.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.82-6.79(m, 2H), 6.55 (d, J=11.5 Hz, 1H), 3.21 (s, 3H), 2.79 (br s, 4H), 1.84(br s, 4H). ¹³C NMR (125 MHz, DMSO-d₆): δ 165.4, 159.1, 157.1 (d, J=3.1Hz), 154.6 (d, J=9.1 Hz), 153.5, 138.4, 132.5, 131.3, 130.2, 118.8,116.3, 113.1 (d, J=18.3 Hz), 107.6 (d, J=22.1 Hz), 40.4, 28.8, 28.1,22.7, 22.4.

Example 36 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-((1-(trifluoromethyl)cyclopropyl)-methoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with(1-(trifluoromethyl)-cyclopropyl)methanol, the title compound wasobtained as a colorless solid (0.28 g, 36%): ¹H NMR (300 MHz, DMSO-d₆) δ12.16 (br s, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.3 Hz, 1H), 4.31(s, 1H), 1.18-0.98 (m, 4H); MS (ES−) m/z: 388.0.1, 390.0 (M-1).

Example 37 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((1s,4s)-4-(trifluoromethyl)cyclohexyl)-oxy)benzamideand5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((1r,4r)-4-(trifluoromethyl)cyclohexyl)-oxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with4-(trifluoromethyl)-cyclohexanol, two steroisomers were obtained bycolumn chromatography, eluting with 15-30% gradient of ethyl acetate(containing 0.2% acetic acid) in hexanes. The first fraction,5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((1s,4s)-4-(trifluoromethyl)cyclohexyl)oxy)-benzamide,colorless solid (0.07 g, 5%): ¹H NMR (300 MHz, CDCl₃) δ 8.68 (br s, 1H),8.11 (d, J=8.1 Hz, 1H), 6.71 (d, J=13.8 Hz, 1H), 4.35-4.22 (m, 1H), 3.42(s, 3H), 2.31-2.03 (m, 4H), 1.69-1.42 (m, 5H); MS (ES−) m/z: 416.1,418.1 (M−1). The second fraction,5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((1r,4r)-4-(trifluoromethyl)-cyclohexyl)-oxy)benzamide, colorless solid(0.59 g, 47%): ¹H NMR (300 MHz, CDCl₃) δ 8.69 (br s, 1H), 8.12 (d, J=8.4Hz, 1H), 6.70 (d, J=13.8 Hz, 1H), 4.71 (dd, J=2.4, 2.7 Hz, 1H), 3.42 (s,3H), 2.22-2.03 (m, 3H), 1.87-1.56 (m, 6H); MS (ES−) m/z: 416.1, 418.1(M−1).

Example 38 Synthesis of4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)-N-(methylsulfonyl)benzamide

Step 1. Preparation of 4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile

To a mixture of adamantan-1-ylmethanol (12.47 g, 75.00 mmol) inanhydrous tetrahydrofuran (100 mL) was added sodium hydride (60% w/w inmineral oil, 3.30 g, 82.50 mmol) at 0° C. The resulting mixture wasstirred at ambient temperature for 2 h, followed by the addition of4-fluoro-3-bromobenzonitrile (15.00 g, 75.00 mmol). Stirring wascontinued at ambient temperature for 17 h, cooled to 0° C. and quenchedwith saturated ammonium chloride solution (20 mL). The volatiles wereremoved by evaporation in vacuo. The residue was washed with water anddiethyl ether to give the title compound as a pale yellow solid (21.00g, 80%): ¹H NMR (300 MHz, CDCl₃) δ 7.80-7.78 (m, 1H), 7.56-7.51 (m, 1H),6.88-6.84 (m, 1H), 3.57 (s, 3H), 2.02 (br s, 3H), 1.73-1.55 (m, 12H).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzonitrile

A reaction mixture of 4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile(1.04 g, 3.00 mmol), potassium carbonate (1.00 g, 7.20 mmol) and(2-methoxypyridin-3-yl)boronic acid (0.92 g, 6.00 mmol) in dioxane (30mL) was degassed three times with nitrogen, thentetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.15 mmol) was addedand the reaction mixture was degassed three further times with nitrogen.The resulting mixture was heated at 90° C. for 19 h, and then thereaction was cooled to ambient temperature,(2-methoxypyridin-3-yr)boronic acid (0.46 g, 3.00 mmol) andtetrakis(triphenylphosphfne)-pailadium(0) (0.09 g, 0.08 mmol) were addedand the reaction was degassed three times with nitrogen and heated at90° C. for further 7 h. After cooling to ambient temperature, thereaction mixture was diluted with ethyl acetate (200 mL) and washed withwater and brine; dried over anhydrous sodium sulfate and concentrated invacuo. Purification of the residue by column chromatography (15% ethylacetate in hexanes) afforded the title compound as a colorless solid(1.11 g, 98%): ¹H NMR (300 MHz, CDCl₃) δ 8.20-8.16 (m, 1H), 7.62-7.48(m, 3H), 6.96-6.91 (m, 2H), 3.87 (s, 3H), 3.48 (s, 2H), 1.89 (br s, 3H),1.68-1.35 (m, 12H); MS (ES+) m/z: 375.2, (M+1).

Step 3. Preparation of4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide

To a solution of4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzonitrile (1.15 g,3.07 mmol) in dimethylsulfoxide (25 mL) and methylene chloride (25 mL)was added potassium carbonate (0.85 g, 6.15 mmol) followed by additionof 35% hydrogen peroxide aqueous solution (5.30 mL, 61.60 mmol)dropwise. The mixture was stirred at ambient temperature for 4 h, thevolatiles were removed by evaporation in vacuo. The residue was dilutedwith water (100 mL). The precipitate was collected by filtration andwashed with water to give the title compound as a colorless solid (0.97g, 80%): ¹H NMR (300 MHz, CDCl₃) δ 8.18-8.15 (m, 1H), 7.84-7.79 (m, 1H),7.71-7.69 (m, 1H), 7.54-7.50 (m, 1H), 6.95-6.91 (m, 2H), 5.85 (br s,2H), 3.87 (s, 3H), 3.49 (s, 2H), 1.89 (br s, 3H), 1.68-1.37 (m, 12H); MS(ES+) m/z: 393.2 (M+1).

Step 4. Preparation of4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)-N-(methylsulfonyl)benzamide

To a solution of4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide (0.39 g,1.00 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (0.09 g,2.25 mmol). The reaction mixture was stirred at ambient temperature for2 h, methanesulfonyl chloride (0.12 mL, 1.54 mmol) was added; stirringwas continued for 46 h at ambient temperature and quenched by additionof 5% hydrochloric acid (1.0 mL). Diluted with ethyl acetate (100 mL)and washed with brine; dried over anhydrous sodium sulfate andconcentrated in vacuo. Purification of the residue by columnchromatography using 10% to 50% gradient ethyl acetate in hexanes toafford the title compound as a colorless solid (0.13 g, 27%): ¹H NMR(300 MHz, CDCl₃) δ 8.73 (br s, 1H), 8.21-8.17 (m, 1H), 7.88-7.83 (m,1H), 7.78-7.65 (m, 1H), 7.55-7.50 (m, 1H), 7.00-6.93 (m, 2H), 3.88 (s,3H), 3.53 (s, 2H), 3.40 (s, 3H), 1.90 (br s, 3H), 1.69-1.31 (m, 12H); MS(ES−) m/z: 469.1 (M−1).

Example 39 Synthesis of4-(adamantan-1-ylmethoxy)-3-cyclopropyl-N-(methylsulfonyl)benzamide

Step 1. Preparation of4-(adamantan-1-ylmethoxy)-3-cyclopropylbenzonitrile

A solution of 4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile (6.93 g,20.00 mmol), cyclopropylboronic acid (2.58 g, 30.00 mmol) and potassiumphosphate (19.10 g, 90.00 mmol) in toluene (100 mL) and water (5 mL) wasbubbled with a nitrogen atmosphere for 10 min, tricyclohexylphosphinetetrafluoroborate (0.74 g, 2.00 mmol) and palladium acetate (0.23 g,1.00 mmol) was added to this reaction mixture. The reaction mixture washeated to 100° C. for 18 h and then cooled to ambient temperature. Water(50 mL) was added and the mixture, extracted with ethyl acetate (100mL×3), the combined organics were washed with brine; dried overanhydrous sodium sulfate and concentrated in vacuo. The residue wastitrated in methanol (50 mL), the solid was filtered and dried to givethe title compound as a colorless solid (5.70 g, 92%): ¹H NMR (300 MHz,CDCl₃) δ 7.43-7.38 (m, 1H), 7.11-7.10 (m, 1H), 6.82-6.78 (m, 1H), 3.52(s, 2H), 2.16-1.98 (m, 4H), 1.00-1.64 (m, 12H), 0.99-0.91 (m, 2H),0.66-0.59 (m, 2H); MS (ES+) m/z: 308.2 (M+1).

Step 2. Preparation of 4-(adamantan-1-ylmethoxy)-3-cyclopropylbenzamide

Following the procedure as described in Example 38 step 3 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzonitrile with4-(adamantan-1-ylmethoxy)-3-cyclopropylbenzonitrile, the title compoundwas obtained as a colorless solid (0.48 g, 97%): ¹H NMR (300 MHz, CDCl₃)δ 7.57-7.53 (m, 1H), 7.37-7.35 (m, 1H), 6.81-6.76 (m, 1H), 5.69 (br s,2H), 3.55 (s, 2H), 2.19-2.09 (m, 1H), 2.04 (br s, 3H), 1.90-1.67 (m,12H), 0.98-0.91 (m, 2H), 0.73-0.66 (m, 2H); MS (ES+) m/z: 326.2 (M+1).

Step 3. Preparation of4-(adamantan-1-ylmethoxy)-3-cyclopropyl-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 38 step 4 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with4-(adamantan-1-ylmethoxy)-3-cyclopropyl-benzamide, the title compoundwas obtained as a colorless solid (0.36 g, 18%): ¹H NMR (300 MHz, CDCl₃)δ 8.45 (br s, 1H), 7.62-7.57 (m, 1H), 7.36-7.34 (m, 1H), 6.85-6.80 (m,1H), 2.58 (s, 2H), 3.41 (s, 3H), 2.19-2.09 (m, 1H), 2.02 (br s, 3H),1.79-1.52 (m, 12H), 0.99-0.91 (m, 2H), 0.71-0.64 (m, 2H); MS (ES−) m/z:402.3 (M−1).

Example 40 Synthesis of 4-(adamantan-1-ylmethoxy)-3-cyclopropyl-N—(N,N-dimethylsulfamoyl)benzamide

Following the procedure as described in Example 38 step 4 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with4-(adamantan-1-ylmethoxy)-3-cyclopropylbenzamide and methanesulfonylchloride with dimethylsulfamoyl chloride, the title compound wasobtained as a colorless solid (0.19 g, 34%): ¹H NMR (300 MHz, CDCl₃) δ8.65 (br s, 1H), 7.64-7.56 (m, 1H), 7.41-7.35 (m, 1H), 6.85-6.77 (m,1H), 3.57 (s, 2H), 3.01 (s, 6H), 2.19-2.08 (m, 1H), 2.02 (br s, 3H),1.79-1.58 (m, 12H), 0.99-0.91 (m, 2H), 0.71-0.64 (m, 2H); MS (ES−) m/z:431.2 (M−1).

Example 41 Synthesis of4-(adamantan-1-ylmethoxy)-3-bromo-N-(methylsulfonyl)benzamide

Step 1. Preparation of 4-(adamantan-1-ylmethoxy)-3-bromobenzamide

Following the procedure as described in Example 38 step 3 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzonitrile with4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile, the title compound wasobtained as a colorless solid (1.80 g, 98%): ¹H NMR (300 MHz, CDCl₃) δ7.99-7.97 (m, 1H), 7.74-7.69 (m, 1H), 6.87-6.83 (m, 1H), 5.86 (br s,2H), 3.57 (s, 2H), 2.02 (br s, 3H), 1.79-1.58 (m, 12H); MS (ES+) m/z:364.1, 366.1 (M+1).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-3-bromo-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 38 step 4 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with4-(adamantan-1-ylmethoxy)-3-bromobenzamide, the title compound wasobtained as a colorless solid (0.17 g, 38%): ¹H NMR (300 MHz, CDCl₃) δ8.88 (br s, 1H), 8.09-8.06 (m, 1H), 7.80-7.72 (m, 1H), 6.93-6.87 (m,1H), 3.61 (s, 2H), 3.43 (s, 3H), 2.04 (br s, 3H), 1.81-1.53 (m, 12H); MS(ES−) m/z: 442.2, 440.2 (M−1).

Example 42 Synthesis of5-chloro-4-((4,4-difluorocyclohexyl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with(4,4-difluorocyclohexyl)-methanol, the title compound was obtained as acolorless solid (0.31 g, 15%): ¹H NMR (300 MHz, CDCl₃) δ 8.70 (br s,1H), 8.09 (d, J=8.1 Hz, 1H), 6.69 (d, J=13.5 Hz, 1H), 3.92 (d, J=6.3 Hz,2H), 3.42 (s, 3H), 2.25-2.11 (m, 2H), 2.04-1.93 (m, 3H), 1.91-1.69 (m,2H), 1.54-1.40 (m, 2H); MS (ES−) m/z: 398.1, 400.1 (M−1).

Example 43 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-(spiro[3,5]nonan-7-ylmethoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol withspiro[3.5]nonan-7-ylmethanol, the title compound was obtained as acolorless solid (0.15 g, 37%): ¹H NMR (300 MHz, CDCl₃) δ 8.69 (br s,1H), 8.08 (d, J=8.1 Hz, 1H), 6.67 (d, J=13.8 Hz, 1H), 3.84 (d, J=6.0 Hz,2H), 3.42 (s, 3H), 1.85-1.65 (m, 11H), 1.36-1.11 (m, 4H); MS (ES−) m/z:402.1, 404.1 (M−1).

Example 44 Synthesis of5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-(spiro[3.5]nonan-7-ylmethoxy)-benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N-(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with spiro[3.5]nonan-7-ylmethanol, the titlecompound was obtained as a colorless solid (0.26 g, 47%): ¹H NMR (300MHz, CDCl₃) δ 8.61 (br s, 1H), 8.05 (d, J=8.4 Hz, 1H), 6.65 (d, J=13.5Hz, 1H), 3.82 (d, J=6.3 Hz, 2H), 3.01 (s, 6H), 1.89-1.65 (m, 11H),1.35-1.04 (m, 4H); MS (ES−) m/z: 431.2, 433.2 (M−1).

Example 45 Synthesis of5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with spiro[2.5]octan-6-ylmethanol, the titlecompound was obtained as a colorless solid (0.17 g, 40%): ¹H NMR (300MHz, CDCl₃) δ 8.65-8.59 (m, 1H), 8.06 (d, J=8.1 Hz, 1H), 6.67 (d, J=13.8Hz, 1H), 3.88 (d, J=6.3 Hz, 2H), 3.01 (s, 6H), 1.95-1.72 (m, 5H),1.34-1.21 (m, 2H), 0.96-0.90 (m, 2H), 0.33-0.26 (m, 2H), 0.22-0.16 (m,2H); MS (ES−) m/z: 417.2, 419.2 (M−1).

Example 46 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-(spiro[2,5]octan-6-ylmethoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol withspiro[2.5]octan-6-ylmethanol, the title compound was obtained as acolorless solid (0.21 g, 53%): ¹H NMR (300 MHz, CDCl₃) δ 8.68 (br s,1H), 8.07 (d, J=8.1 Hz, 1H), 6.68 (d, J=13.8 Hz, 1H), 3.89 (d, J=6.3 Hz,2H), 3.40 (s, 3H), 1.96-1.71 (m, 5H), 1.33-1.19 (m, 2H), 0.99-0.86 (m,2H), 0.33-0.26 (m, 2H), 0.23-0.15 (m, 2H); MS (ES−) m/z: 388.2, 390.2(M−1).

Example 47 Synthesis of4-((adamantan-1-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of methyl 4-bromo-2-chloro-5-fluorobenzoate

To a solution of 4-bromo-2-chloro-5-fluorobenzoic acid (25.40 g, 100.00mmol) in methanol (300 mL) was added thionyl chloride (0.8 mL, 11.00mmol) over 5 min at 0° C. The reaction mixture was heated to reflux for8 h and then neutralized by slow addition of sodium bicarbonate (5.0 g)at 0° C. The solid was filtered out and washed with ethyl acetate (50mL), the combined filtrate was concentrated in vacuo to afford the titlecompound as a pale yellow solid (24.7 g, 92%): ¹H NMR (300 MHz, CDCl₃) δ7.68-7.60 (m, 2H), 3.91 (s, 3H).

Step 2. Preparation of (4-bromo-2-chloro-5-fluorophenyl)methanol

To a solution of methyl 4-bromo-2-chloro-5-fluorobenzoate (18.00 g,67.28 mmol) in tetrahydrofuran (100 mL) was added methanol (3.0 mL,74.15 mmol), followed by the addition of lithium borohydride solution(4.0 M in tetrahydrofuran, 33.7 mL, 134.80 mmol) at 0° C. over 30 min.The reaction mixture was stirred for further 10 min at 0° C., and thenat ambient temperature for 20 h; 5% sodium hydroxide solution (100 mL)was added to the reaction mixture slowly at 0° C. After stirring for 30min. the reaction mixture was extracted with ethyl acetate (200 mL×3).The organic layer was washed with brine, and concentrated in vacuo toafford the title compound as a pale yellow solid (16.00 g, 99%): ¹H NMR(300 MHz, CDCl₃) δ 7.51 (d, J=6.0 Hz, 1H), 7.30 (d, J=9.0 Hz, 1H), 4.69(s, 2H), 2.08 (s, 1H).

Step 3. Preparation of 4-bromo-2-chloro-5-fluorobenzyl2,2,2-trichloroacetimidate

To a solution of (4-bromo-2-chloro-5-fluorophenyl)methanol (3.95 g,16.49 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.5 mL, 3.34mmol) in methylene chloride (30 mL) was added trichloroacetonitrile (,2.50 mL, 24.93 mmol) over 5 min at 0° C., stirring was continued for 4 hat 0° C. After concentrated in vacuo, the residue was purified by columnchromatography eluting with 5% ethyl acetate in hexanes to give4-bromo-2-chloro-5-fluorobenzyl 2,2,2-trichloroacetimidate as acolorless solid (5.80 g, 91%): δ 8.49 (s, 1H), 7.59 (d, J=6.3 Hz, 1H),7.32 (d, J=9.0 Hz, 1H), 5.37 (s, 2H).

Step 4. Preparation of1-((4-bromo-2-chloro-5-fluorobenzyl)oxy)adamantane

To a solution of 4-bromo-2-chloro-5-fluorobenzyl2,2,2-trichloroacetimidate (3.95 g, 16.49 mmol) and 1-adamantanol (0.65g, 4.26 mmol) in methylene chloride (15 mL) and cyclohexane (30 mL) wasadded trifluoromethanesulfonic acid (0.04 mL, 0.45 mmol) at 0° C. Thereaction mixture was stirred for 56 h at ambient temperature andquenched by addition of saturated sodium bicarbonate solution (10 mL),and then diluted with methylene chloride (100 mL). The organic layer wasseparated and washed with brine; dried over anhydrous sodium sulfate andconcentrated in vacuo. Purification of the residue by columnchromatography (5% ethyl acetate in hexanes) and recrystallization frommethanol afforded 1-((4-bromo-2-chloro-5-fluorobenzyl)-oxy)adamantane asa colorless solid (0.70 g, 43%): ¹H NMR (300 MHz, CDCl₃) δ 7.47 (d,J=6.3 Hz, 1H), 7.37 (d, J=9.3 Hz, 1H), 4.48 (s, 2H), 2.16 (br s, 3H),1.82-1.80 (m, 6H), 1.70-1.55 (m, 6H).

Step 5. Preparation of4-((adamantan-1-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

A mixture of 1-((4-bromo-2-chloro-5-fluorobenzyl)oxy)adamantane (0.37 g,1.00 mmol), methanesulfonamide (0.29 g, 3.00 mmol),molybdenumhexacarbonyl (0.27 g, 1.00 mmol) and triethylamine (0.6 mL,4.30 mmol) in dioxane was purged with nitrogen for 5 min, xantphos (0.10g, 0.18 mmol) and palladium acetate (0.02 g, 2.00 mmol) were added tothe reaction mixture. The reaction mixture was heated at 100° C. for 1 hunder microwave irradiation (300 psi) and then cooled to ambienttemperature, diluted with methylene chloride (100 mL) and saturatedammonium chloride (20 mL). The organic layer was washed with brine;dried over anhydrous sodium sulfate and concentrated in vacuo.Purification of the residue by column chromatography (10% to 30%gradient ethyl acetate in hexanes) afforded the title compound as acolorless solid (0.12 g, 28%): ¹H NMR (300 MHz, CDCl₃) δ 8.74 (br s,1H), 8.01 (d, J=6.9 Hz, 1H), 7.49 (d, J=12.9 Hz, 1H), 4.57 (s, 2H), 3.41(s, 3H), 2.18 (br s, 3H), 1.84-1.81 (m, 6H), 1.70-1.54 (m, 6H); MS (ES−)m/z: 414.1, 416.1 (M−1).

Example 48 Synthesis of4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of2-((4-bromo-2-chloro-5-fluorobenzyl)oxy)adamantane

Following the procedure as described in Example 47 step 4 and makingvariations as required to replace 1-adamantanol with 2-adamantanol, thetitle compound was obtained as a colorless solid (1.07 g, 39%): ¹H NMR(300 MHz, CDCl₃) δ 7.49 (d, J=6.0 Hz, 1H), 7.40 (d, J=9.3 Hz, 1H), 4.49(s, 2H), 3.57 (br s, 1H), 2.55-1.49 (m, 14H); MS (ES+) m/z: 373.0, 375.0(M+1).

Step 2. Preparation of4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)-benzamide

Following the procedure as described in preparation of Example 47 step 5and making variation as required to replace1-((4-bromo-2-chloro-5-fluorobenzyl)oxy)adamantane with2-((4-bromo-2-chloro-5-fluorobenzyl)oxy)adamantane, the title compoundwas obtained as a colorless solid (0.68 g, 81%): ¹H NMR (300 MHz, CDCl₃)δ 8.80 (br s, 1H), 8.02 (d, J=6.9 Hz, 1H), 7.52 (d, J=12.9 Hz, 1H), 4.58(s, 2H), 3.60 (br s, 1H), 3.41 (s, 3H), 2.11-1.50 (m, 14H); MS (ES−)m/z: 414.2, 416.2 (M−1).

Example 49 Synthesis of4-((adamantan-2-yloxy)methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

To a solution of4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)-benzamide(0.30 g, 0.72 mmol), cyclopropylboronic acid (0.40 g, 4.65 mmol) andpotassium phosphate (2.55 g, 12.00 mmol) in toluene (10 mL) and water(0.5 mL) was bubbled with a nitrogen atmosphere for 10 min,tricyclohexylphosphine tetrafluoroborate (0.17 g, 0.48 mmol) andpalladium acetate (0.05 g, 0.22 mmol) was added to this reactionmixture. The reaction mixture was heated to 100° C. for 18 h under anitrogen atmosphere and then cooled to ambient temperature. 5% aqueoushydrochloric acid (20 mL) was added and the mixture was extracted withethyl acetate (100 mL×3), the combined organics were washed with brine;dried over anhydrous sodium sulfate and concentrated in vacuo.Purification of the residue by column chromatography (10% to 30%gradient ethyl acetate in hexanes) afforded the title compound as acolorless solid (0.19 g, 62%): ¹H NMR (300 MHz, CDCl₃) δ 8.81 (br s,1H), 7.69 (d, J=7.8 Hz, 1H), 7.40 (d, J=13.5 Hz, 1H), 4.71 (s, 2H), 3.60(br s, 1H), 3.41 (s, 3H), 2.16-2.03 (m, 4H), 1.90-1.51 (m, 11H),0.97-0.90 (m, 2H), 0.68-0.62 (m, 2H); MS (ES−) m/z: 420.35 (M−1).

Example 50 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid

To a solution of 1-adamantane methanol (28.50 g, 171.40 mmol) inanhydrous dimethylsulfoxide (300 ml) in a 2 L two necked flask fittedwith a mechanic stirrer was added potassium tert-butoxide (48.10 g,428.50 mmol) and the suspension was stirred at ambient temperature for30 minutes. 5-chloro-2,4-difluorobenzoic acid (33.00 g, 171.40 mmol) wasadded to the reaction mixture in 5 minutes. During this period, themixture became hot (do not use ice bath) and yellow gummy solid wasformed. Stirring was continued for 2 h. The reaction mixture wasacidified to pH=1 with cold aqueous hydrochloric acid solution (1N),followed by addition of 25% aqueous ammonium chloride solution (400 mL).The solid was filtered and washed with water and a mixture ofhexanes/diethyl ether (3/1, v/v); dried to give crude product (˜75%p-substituted and ˜25% o-substituted by ¹H NMR; 95% p-substituted byHPLC at 254 nm) as off-white solid (32 g, 55%), which was used for nextstep without further purification. Additional 15 g of light yellow solid(87% by HPLC) was obtained from the filtrate. The pure product can beobtained by recrystallization from 2-propanol: ¹H NMR (300 MHz, DMSO-d₆)δ 13.11 (s, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.17 (d, J=12.7 Hz, 1H), 3.71(s, 2H), 1.99 (s, 3H), 1.74-1.63 (m, 12H);

Step 2. Preparation of tert-butyl4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoate

To a suspension of 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoicacid (30.00 g, 88.54 mmol) and N,N-dimethylpyridin-4-amine (0.50 g, 4.16mmol) in tert-butanol (200 mL) was added di-tert-butyldicarbonate (40.60g, 186.02 mmol). The reaction mixture was heated at 50° C. for 6 h.Additional di-tert-butyldicarbonate (20.30 g, 93.01 mmol) was added;stirring was continued for 17 h at 50° C. and concentrated in vacuo. Theresidue was titrated in methanol (100 mL), the solid was collected byfiltration and dried to give the title compound as a colorless solid(25.00 g, 71%): ¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J=7.8 Hz, 1H), 6.59(d, J=12.3 Hz, 1H), 3.53 (s, 2H), 2.01 (s, 3H), 1.78-1.61 (m, 12H), 1.55(s, 9H).

Step 3. Preparation of tert-butyl4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate

To a solution of tert-butyl4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoate (15.80 g, 40.00mmol), cyclopropylboronic acid (5.16 g, 60.00 mmol) and potassiumphosphate (38.20 g, 180.00 mmol) in toluene (160 mL) and water (8 mL)was bubbled with a nitrogen atmosphere for 10 min,tricyclohexylphosphine tetrafluoroborate (1.47 g, 3.99 mmol) andpalladium acetate (0.45 g, 2.00 mmol) was added to this reactionmixture. The reaction mixture was heated to 100° C. for 18 h and thencooled to ambient temperature. Water (100 mL) was added and the mixturewas extracted with ethyl acetate (100 mL×3), the combined organics werewashed with brine; dried over anhydrous sodium sulfate and concentratedin vacuo. Purification of the residue by column chromatography (5% ethylacetate in hexanes) afforded the title compound as a colorless solid(13.8 g, 86%): ¹H NMR (300 MHz, CDCl₃) δ 7.37 (d, J=8.4 Hz, 1H), 6.47(d, J=12.9 Hz, 1H), 3.49 (s, 2H), 2.05-1.95 (m, 4H), 1.78-1.61 (m, 12H),1.55 (s, 9H), 0.91-0.84 (m, 2H), 0.64-0.58 (m, 2H).

Step 4. Preparation of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid

To a solution of tert-butyl4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate (13.80 g, 34.45mmol) in dichloromethane (50 mL), was added trifluoroacetic acid (25ml). The reaction mixture was stirred at ambient temperature for 2 hoursand then concentrated in vacuo. The residue was titrated in methanol (50mL), the solid was collected by filtration and dried to give the titlecompound as a colorless solid (10.10 g, 85%): ¹H NMR (300 MHz, DMSO-d₆)δ 12.77 (br s, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.83 (d, J=13.2 Hz, 1H),3.59 (s, 2H), 2.04-1.92 (m, 4H), 1.71-1.58 (m, 12H), 0.91-0.83 (m, 2H),0.59-0.52 (m, 2H).

Step 5. Preparation of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-benzamide

To a stirred solution of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid (0.52 g,1.50 mmol) in dichloromethane (40 mL) and tetrahydrofuran (40 mL) wereadded N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.43g, 2.24 mmol), and 4-(dimethylamino)pyridine (0.42 g, 3.43 mmol). Thereaction mixture was stirred at ambient temperature for 10 min,methanesulfonamide (0.22 g, 2.28 mmol) was added and stirring continuedat ambient temperature for 36 h. 5% aqueous hydrochloric acid (10 mL)were added and then diluted with ethyl acetate (200 mL), washed withwater and brine; dried over anhydrous sodium sulfate and concentrated invacuo. Purification of the residue by column chromatography (10% to 30%gradient ethyl acetate in hexanes) afforded the title compound as acolorless solid (0.45 g, 70%): ¹H NMR (300 MHz, CDCl₃) δ 8.72 (d, J=16.2Hz, 1H), 7.58 (d, J=9.3 Hz, 1H), 6.56 (d, J=14.7 Hz, 1H), 3.56 (s, 2H),3.41 (s, 3H), 2.09-2.00 (m, 4H), 1.81-1.58 (m, 12H), 0.99-0.91 (m, 2H),0.70-0.62 (m, 2H); MS (ES−) m/z: 420.2 (M−1).

Example 51 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(N-methylsulfamoyl)benzamide

Following the procedure as described in preparation of Example 50 step 5and making variation as required to replace methanesulfonamide with(methylsulfamoyl)amine, the title compound was obtained as a colorlesssolid (0.17 g, 38%): ¹H NMR (300 MHz, CDCl₃) δ 8.71 (d, J=15.9 Hz, 1H),7.56 (d, J=9.0 Hz, 1H), 6.56 (d, J=14.4 Hz, 1H), 5.35-5.22 (m, 1H), 3.55(s, 2H), 2.76 (d, J=5.4 Hz, 3H), 2.09-1.99 (m, 4H), 1.81-1.59 (m, 12H),0.99-0.91 (m, 2H), 0.70-0.62 (m, 2H); MS (ES−) m/z: 435.3 (M−1).

Example 52 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in preparation of Example 50 step 5and making variation as required to replace methanesulfonamide withazetidine-1-sulfonamide, the title compound was obtained as a colorlesssolid (0.17 g, 37%): ¹H NMR (300 MHz, CDCl₃) δ 8.63 (br s, 1H), 7.58 (d,J=9.0 Hz, 1H), 6.54 (d, J=14.4 Hz, 1H), 4.22 (t, J=7.8 Hz, 4H), 3.54 (s,2H), 3.00-2.19 (m, 2H), 2.08-1.97 (m, 4H), 1.79-1.57 (m, 12H), 0.96-0.89(m, 2H), 0.68-0.62 (m, 2H); MS (ES−) m/z: 461.3 (M−1).

Example 53 Synthesis of5-chloro-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with4,4-difluoro-1-(hydroxymethyl)adamantane, the title compound wasobtained as a colorless solid (0.47 g, 42%): ¹H NMR (300 MHz, CDCl₃) δ8.69 (br s, 1H), 8.06 (d, J=8.4 Hz, 1H), 6.65 (d, J=13.8 Hz, 1H), 3.61(s, 2H), 3.39 (s, 3H), 2.28 (br s, 2H), 2.05-1.87 (m, 5H), 1.78-1.66 (m,6H); MS (ES−) m/z: 450.2, 452.2 (M−1).

Example 54 Synthesis of5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 49 and making variationas required to replace4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamidewith5-chloro-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide,the title compound was obtained as a colorless solid (0.32 g, 86%): ¹HNMR (300 MHz, CDCl₃) δ 8.69 (br s, 1H), 7.59 (d, J=9.0 Hz, 1H), 6.53 (d,J=14.1 Hz, 1H), 3.59 (s, 2H), 3.39 (s, 3H), 2.28 (br s, 2H), 2.08-1.92(m, 6H), 1.53-1.51 (m, 6H), 0.97-0.89 (m, 2H), 0.66-0.60 (m, 2H); MS(ES−) m/z: 456.2 (M−1).

Example 55 Synthesis of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(spiro[2.5]octan-6-ylmethoxy)benzamideand 2-fluoro-N-(methylsulfonyl)-4-(spiro[2.5]octan-6-ylmethoxy)benzamide

Following the procedure as described in Example 49 and making variationas required to replace4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamidewith5-chloro-2-fluoro-N-(methylsulfonyl)-4-(spiro[2.5]-octan-6-ylmethoxy)benzamide,two compounds were obtained by column chromatography, eluting with10-30% gradient of ethyl acetate (containing 0.2% acetic acid) inhexanes. The first fraction,5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(spiro[2.5]octan-6-ylmethoxy)benzamide,colorless solid (0.25 g, 28%): ¹H NMR (300 MHz, CDCl₃) δ 8.79 (br s,1H), 7.54 (d, J=9.3 Hz, 1H), 6.56 (d, J=14.4 Hz, 1H), 3.85 (d, J=6.0 Hz,2H), 3.39 (s, 3H), 2.08-1.72 (m, 6H), 1.36-1.22 (m, 2H), 0.96-0.88 (m,4H), 0.67-0.62 (m, 2H), 0.33-0.15 (m, 4H); MS (ES−) m/z: 394.3 (M−1).The second fraction,2-fluoro-N-(methylsulfonyl)-4-(spiro[2.5]octan-6-ylmethoxy)benzamide,colorless solid (0.1 g, 12%): ¹H NMR (300 MHz, CDCl₃) δ 8.71 (br s, 1H),8.05-7.98 (m, 1H), 6.84-6.79 (m, 1H), 6.68-6.61 (m, 1H), 3.84 (d, J=6.0Hz, 2H), 3.40 (s, 3H), 1.91-1.69 (m, 5H), 1.30-1.16 (m, 2H), 0.97-0.89(m, 2H), 0.33-0.15 (m, 4H); MS (ES−) m/z: 354.3 (M−1).

Example 56 Synthesis of5-cyclopropyl-4-((4,4-difluorocyclohexyl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 49 and making variationas required to replace4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamidewith5-chloro-4-((4,4-difluorocyclohexyl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide,the title compound was obtained as a colorless solid (0.04 g, 13%): ¹HNMR (300 MHz, CDCl₃) δ 8.69 (d, J=15.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H),6.55 (d, J=14.4 Hz, 1H), 3.88 (d, J=9.0 Hz, 2H), 3.39 (s, 3H), 2.25-2.11(m, 2H), 2.04-1.66 (m, 6H), 1.54-1.41 (m, 2H), 0.97-0.89 (m, 2H),0.67-0.61 (m, 2H); MS (ES−) m/z: 404.1 (M−1).

Example 57 Synthesis of5-chloro-4-(2-cycloheptylethoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with cycloheptylmethanol,the title compound was obtained as a colorless solid (0.12 g, 32%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.06 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.21 (d,J=12.5 Hz, 1H), 3.91 (d, J=6.5 Hz, 2H), 3.31 (s, 3H), 1.98-1.21 (m,13H); MS (ES−) m/z 376.1, 378.1 (M−1).

Example 58 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-((4-pentylbicyclo[2.2.2]octan-1-yl)methoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with(4-pentylbicyclo[2.2.2]octan-1-yl)-methanol, the title compound wasobtained as a colorless solid (0.17 g, 49%): ¹H NMR (300 MHz, DMSO-d₆) δ12.10 (s, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.21 (d, J=12.4 Hz, 1H), 3.76 (s,2H), 3.35 (s, 3H), 1.51-1.06 (m, 20H), 0.85 (t, J=6.9 Hz, 3H); MS (ES−)m/z 458.2, 460.1 (M−1).

Example 59 Synthesis oftrans-5-chloro-2-fluoro-4-((4-isopropylcyclohexyl)oxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol withtrans-4-isopropylcyclohexanol, the title compound was obtained as acolorless solid (0.14 g, 36%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.08 (s,1H), 7.76 (d, J=7.6 Hz, 1H), 7.35 (d, J=12.8 Hz, 1H), 4.49 (m, 1H), 3.35(s, 3H), 2.11-2.08 (m, 2H), 1.75-1.71 (m, 2H), 1.48-1.13 (m, 6H), 0.86(d, J=6.8 Hz, 6H); MS (ES−) m/z 390.1, 392.1 (M−1).

Example 60 Synthesis of5-chloro-4-(((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methanol, the titlecompound was obtained as a colorless solid (0.15 g, 37%). ¹H NMR (300MHz, DMSO-d₆) δ 12.12 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.24 (d, J=12.5Hz, 1H), 5.71-5.70 (m, 1H), 4.64 (s, 2H), 3.35 (s, 3H), 2.43-2.33 (m,5H), 1.27 (s, 3H), 1.10-1.08 (m, 1H), 0.76 (m, 3H); MS (ES−) m/z 400.1,402.3 (M−1).

Example 61 Synthesis of5-chloro-4-((3-chloroadamantan-1-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with3-chloroadamantan-1-yl methanol, the title compound was obtained as acolorless solid (0.26 g, 29%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.12 (s,1H), 7.78 (d, J=7.5 Hz, 1H), 7.24 (d, J=12.4 Hz, 1H), 3.82 (s, 2H), 3.35(s, 3H), 2.22-2.04 (m, 8H), 1.65-1.54 (m, 6H); MS (ES−) m/z 448.0, 450.0(M−1).

Example 62 Synthesis of5-chloro-4-(cyclohexyloxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with cyclohexanol, thetitle compound was obtained as a colorless solid (0.03 g, 9%): ¹H NMR(300 MHz, DMSO-d₆) δ 12.03 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.29 (d,J=12.7 Hz, 1H), 4.64-4.57 (m, 1H), 3.95-3.88 (m, 2H), 3.31 (s, 3H),1.88-1.82 (m, 2H), 1.69-1.64 (m, 2H), 1.54-1.27 (m, 6H); MS (ES−) m/z348.1, 350.1 (M−1).

Example 63 Synthesis oftrans-5-chloro-2-fluoro-N-(methylsulfonyl)-4-((4-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol withtrans-4-(trifluoromethyl)cyclohexyl)-methanol, the title compound wasobtained as a colorless solid (0.178 g, 41%): ¹H NMR (300 MHz, DMSO-d₆)δ 12.12 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.4 Hz, 1H), 3.99(d, J=6.1 Hz, 2H), 3.35 (s, 3H), 2.29-2.18 (m, 1H), 1.94-1.81 (m, 5H),1.36-1.09 (m, 4H); MS (ES−) m/z 430.1, 432.1 (M−1).

Example 64 Synthesis of5-chloro-4-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol, the titlecompound was obtained as a colorless solid (0.08 g, 20%). ¹H NMR (300MHz, DMSO-d₆) δ 12.09 (s, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.27 (d, J=12.5Hz, 1H), 4.12-4.00 (m, 2H), 3.35 (s, 3H), 2.57-2.04 (m, 1H), 2.10-1.85(m, 5H), 1.61-1.48 (m, 1H), 1.18 (s, 3H), 1.00 (m, 3H), 0.99-0.95 (m,1H); MS (ES−) m/z 402.1, 404.1 (M−1).

Example 65 Synthesis of5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Step 1. Preparation of 7-hydroxy-2,2-dimethylchroman-4-one

To a solution of 2,4-dihydroxy acetophenone (6.00 g, 39.4 mmol) andpyrrolidine (15.0 mL, 181 mmol) in toluene (200 mL), acetone (22.9 g,394 mmol) was added. After heated to reflux for 16 hrs, the solventswere removed and the residue was added HCl (2.0 N, 100 mL) and brine(200 mL) then the mixture was extracted with EtOAc (150×5 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude product was purified by SGC(eluting with petroleum ether/ethyl acetate=6/1) to give target compound(2.56 g, 33%) as a brown yellow solid. LCMS (ESI) m/z: 191.1 [M−H]⁺;¹H-NMR (500 MHz, CDCl₃): δ 7.79 (d, J=8.0 Hz, 1H), 6.49 (dd, J=8.5, 2.0Hz, 1H), 6.36 (d, J=2.0 Hz, 1H), 2.68 (s, 2H), 1.45 (s, 6H).

Step 2. Preparation of 2,2-dimethylchroman-7-ol

A mixture of 7-hydroxy-2,2-dimethylchroman-4-one (500 mg, 2.60 mmol) andHCl (conc. 10 mL) in MeOH (30 mL) was stirred at 0° C. for 10 min, thenzinc power (300 mg) was added slowly. After stirring at room temperaturefor 16 hrs, the solvents were removed under reduced pressure and themixture was extracted with EtOAc (150×3 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated.The residue was purified by reverse phase column falsh (28%-35% MeCN in0.5% NH₄HCO₃) to give target product of 2,2-dimethylchroman-7-ol (290mg, 62%) as a brown yellow solid. LCMS (ESI) m/z: 177.1 [M−H]⁺; ¹H-NMR(500 MHz, CDCl₃): δ 6.89 (d, J=8.0 Hz, 1H), 6.34 (dd, J=8.5, 2.5 Hz,1H), 6.27 (d, J=2.5 Hz, 1H), 4.70 (s, 1H), 2.69 (t, J=13.5, 7.0 Hz, 2H),1.77 (t, J=13.5, 7.0 Hz, 2H), 1.32 (s, 6H).

Step 3. Preparation of tert-butyl5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoate

A mixture of 2,2-dimethylchroman-7-ol (100 mg, 0.561 mmol), tert-butyl4-(bromomethyl)-5-chloro-2-fluorobenzoate (191 mg, 0.590 mmol) andpotassium carbonate (194 mg, 1.40 mmol) in acetone (30 mL) was stirredat 50° C. for 16 hrs. After cooling to room temperature, the mixture wasextracted with EtOAc (150×5 mL). The combined orgaic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give thecrude product which was used in next step without further purification(290 mg, crude). LCMS (ESI) m/z: 420.8 [M+H].

Step 4. Preparation of5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid

A mixture of tert-butyl5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoate (290mg, 0.689 mmol) and trifluoroacetic acid (10 mL) in DCM (10 mL) wasstirred at room temperature for 16 hrs. The solvents were removed andthe residue was extracted with EtOAc (150×3 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by reverse phase combiflash(15%-19% MeCN in 0.5% NH₄HCO₃) to give target product of5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid(100 mg, 49%) as a white solid. LCMS (ESI) m/z: 364.9 [M+H]⁺.

Step 5. Preparation of5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

A mixture of5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid(50 mg, 0.14 mmol), dimethyl(sulfamoyl)amine (26 mg, 0.21 mmol),N,N-Diisopropylethylamine (54 mg, 0.42 mmol) and2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (106 mg, 0.28 mmol) in DMF (2.5 mL) was stirred atroom temperature for 16 hrs. The mixture was diluted with HCl (2.0 N, 20mL) and extracted with EtOAc (50×3 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by reverse phase combiflash (15%-25% MeCN in 0.5%NH₄HCO₃) to give target product (11.8 mg, 18%) as a white solid. LCMS(ESI) Method A: RT=5.57 min, m/z: 471.2 [M+H]; ¹H-NMR (500 MHz,MeOH-d₄,): δ 7.62 (d, J=6.0 Hz, 1H), 7.31 (d, J=10.5 Hz, 1H), 6.87 (d,J=8.5 Hz, 1H), 6.40 (dd, J=8.0, 2.5 Hz, 1H), 6.24 (d, J=2.5 Hz, 1H),5.02 (s, 2H), 2.86 (s, 6H), 2.61 (t, J=7.0 Hz, 2H), 1.68 (t, J=7.0 Hz,2H), 1.20 (s, 6H).

Example 66 Synthesis of5-chloro-4-(cycloheptylmethoxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with cycloheptylmethanol, the title compound wasobtained as a colorless solid (0.08 g, 20%): ¹H NMR (300 MHz, DMSO-d₆) δ11.77 (s, 1H), 7.72 (d, J=7.4 Hz, 1H), 7.24 (d, J=12.3 Hz, 1H), 3.94 (d,J=6.6 Hz, 2H), 2.87 (s, 6H), 2.00-1.25 (m, 13H); MS (ES−) m/z 405.1,407.1 (M−1).

Example 67 Synthesis of5-chloro-4-(2-cyclohexylethoxy)-N—(N,N-dimethyl-sulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 2-cyclohexylethanol, the title compound wasobtained as a colorless solid (0.09 g, 22%): ¹H NMR (300 MHz, DMSO-d₆) δ11.77 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.4 Hz, 1H), 4.17 (t,J=6.6 Hz, 2H), 2.87 (s, 6H), 1.76-1.60 (m, 7H), 1.54-1.42 (m, 1H),1.28-1.11 (m, 3H), 1.02-0.90 (m, 2H); MS (ES−) m/z 405.1, 407.1 (M−1).

Example 68 Synthesis of5-chloro-4-(2-cyclohexylmethoxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with cyclohexylmethanol, the title compound wasobtained as a colorless solid (0.11 g, 28%): ¹H NMR (300 MHz, DMSO-d₆) δ11.77 (s, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.23 (d, J=12.4 Hz, 1H), 3.96 (d,J=5.8 Hz, 2H), 2.87 (s, 6H), 1.84-1.62 (m, 6H), 1.30-1.04 (m, 5H); MS(ES−) m/z 391.1, 393.1 (M−1).

Example 69 Synthesis of5-chloro-4-(cyclopentylmethoxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with cyclopentylmethanol, the title compound wasobtained as a colorless solid (0.12 g, 32%): ¹H NMR (300 MHz, DMSO-d₆) δ11.77 (s, 1H), 7.73 (d, J=7.4 Hz, 1H), 7.24 (d, J=12.4 Hz, 1H), 4.03 (d,J=6.8 Hz, 2H), 2.87 (s, 6H), 2.39-2.29 (m, 1H), 1.82-1.72 (m, 2H),1.65-1.51 (m, 4H), 1.38-1.30 (m, 2H); MS (ES−) m/z 377.1, 379.1 (M−1).

Example 70 Synthesis oftrans-5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-((4-isopropylcyclohexyl)oxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with trans-4-isopropylcyclohexanol, the titlecompound was obtained as a colorless solid (0.10 g, 24%): ¹H NMR (300MHz, DMSO-d₆) δ 11.75 (s, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.34 (d, J=12.5Hz, 1H), 4.53-4.43 (m, 1H), 2.87 (s, 6H), 2.11-2.07 (m, 2H), 1.75-1.71(m, 2H), 1.50-1.20 (m, 3H), 1.24-1.07 (m, 3H), 0.86 (d, J=6.8 Hz, 6H);MS (ES−) m/z 419.1, 421.1 (M−1).

Example 71 Synthesis oftrans-5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-((4-isopropylcyclohexyl)-oxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 2-cyclopentylethanol, the title compound wasobtained as a colorless solid (0.11 g, 29%): ¹H NMR (300 MHz, DMSO-d₆) δ11.77 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.25 (d, J=12.4 Hz, 1H), 4.16 (t,J=6.5 Hz, 2H), 2.87 (s, 6H), 1.99-1.88 (m, 1H), 1.82-1.74 (m, 4H),1.65-1.43 (m, 4H), 1.24-1.09 (m, 2H); MS (ES−) m/z 391.1, 393.1 (M−1).

Example 72 Synthesis of 5-chloro-4-(((1R,2s,3S,5s,7s)-5-chloroadamantan-2-yl)oxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamideand 5-chloro-4-(((1R,2r, 3S, 5s,7s)-5-chloroadamantan-2-yl)oxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 5-chloroadamantan-2-ol, two diasterromerswere obtained by silica gel column chromatography using 10-50% gradientethyl acetate (containing 0.2% acetic acid) in hexanes.5-chloro-4-(((1R,2s,3S,5s,7s)-5-chloroadamantan-2-yl)oxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamideand5-chloro-4-(((1R,2r,3S,5s,7s)-5-chloroadamantan-2-yl)oxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide.Data for first eluting diastereomer: a colorless solid (0.02 g, 14%). ¹HNMR (300 MHz, DMSO-d₆) δ 11.76 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.39 (d,J=12.5 Hz, 1H), 4.78-4.75 (m, 1H), 2.87 (s, 6H), 2.41-2.32 (m, 4H), 2.10(brs, 3H), 1.96-1.92 (m, 2H), 1.77 (br s, 4H); MS (ES−) m/z 463.1, 465.1(M−1). Data for second eluting diastereomer: a colorless solid (0.003 g,2%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.76 (s, 1H), 7.75 (d, J=7.5 Hz, 1H),7.38 (d, J=12.3 Hz, 1H), 4.91-4.87 (m, 1H), 2.87 (s, 6H), 2.35-2.11 (m,9H), 1.99-1.95 (m, 2H), 1.53-1.49 (m, 2H); MS (ES−) m/z 463.1, 465.1(M−1).

Example 73 Synthesis of5-chloro-4-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methoxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]-heptan-2-yl)methanol, the titlecompound was obtained as a colorless solid (0.12 g, 29%): ¹H NMR (300MHz, DMSO-d₆) 11.76 (s, 1H), 7.72 (d, J=6.1 Hz, 1H), 7.26 (d, J=13.2 Hz,1H), 4.12-4.05 (m, 2H), 2.87 (s, 6H), 2.38-2.37 (m, 1H), 2.13-1.90 (m,6H), 1.56 (m, 1H), 1.18 (s, 3H), 1.00-0.92 (m, 4H); MS (ES−) m/z 431.1,433.1 (M−1).

Example 74 Synthesis of5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluoro-N-(N-methylsulfamoyl)benzamide

A mixture of5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid(50 mg, 0.14 mmol), methyl(sulfamoyl)amine (23 mg, 0.21 mmol),1-ethyl-(3-dimethylamino-propyl)carbodiimide hydrochloride (40 mg, 0.21mmol) and 4-dimethylaminopyridine (26 mg, 0.21 mmol) in DCM (20 mL) wasstirred at room temperature for 16 hrs. The mixture was diluted with HCl(2.0 N, 20 mL) and extracted with EtOAc (50×3 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by reverse phase Combiflash(18%-25% MeCN in 0.5% NH₄HCO₃) to give target product (35.4 mg, 56%) asa pale yellow solid. LCMS (ESI) Method A: RT=5.78 min, m/z: 456.7[M+H]⁺; ¹H-NMR (500 MHz, MeOH-d₄,): δ 7.77 (d, J=6.0 Hz, 1H), 7.42 (d,J=10.5 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.52 (dd, J=9.0, 2.5 Hz, 1H),6.36 (d, J=2.5 Hz, 1H), 5.14 (s, 2H), 2.74 (t, J=6.5 Hz, 2H), 2.71 (s,3H), 1.80 (t, J=6.5 Hz, 2H), 1.32 (s, 6H).

Example 75 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-(spiro[5.5]undecan-3-yloxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol withspiro[5.5]undecan-3-ol, the title compound was obtained as a colorlesssolid (0.08 g, 20%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.06 (s, 1H), 7.76 (d,J=7.6 Hz, 1H), 7.31 (d, J=12.8 Hz, 1H), 4.68-4.61 (m, 1H), 3.33 (s, 3H),1.83-1.74 (m, 2H), 1.65-1.52 (m, 4H), 1.38-1.23 (m, 12H); MS (ES−) m/z416.2, 418.2 (M−1).

Example 76 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-(spiro[4.5]decan-8-yloxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with spiro[4.5]decan-8-ol,the title compound was obtained as a colorless solid (0.06 g, 15%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.07 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.33 (d,J=12.8 Hz, 1H), 4.69-4.61 (m, 1H), 3.33 (s, 3H), 1.88-1.79 (m, 2H),1.65-1.51 (m, 8H), 1.45-1.31 (m, 6H); MS (ES−) m/z 402.1, 403.1

(M−1).

Example 77 Synthesis ofcis-5-chloro-2-fluoro-N-(methylsulfonyl)-4-((4-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with(cis-4-(trifluoromethyl)cyclohexyl)-methanol, the title compound wasobtained as a colorless solid (0.09 g, 14%): ¹H NMR (300 MHz, DMSO-d₆) δ12.10 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.33 (d, J=12.6 Hz, 1H), 4.14 (d,J=7.2 Hz, 2H), 3.35 (s, 3H), 2.29-2.18 (m, 1H), 2.14-2.12 (m, 1H),1.76-1.50 (m, 8H); MS (ES−) m/z 430.1, 432.1 (M−1).

Example 78 Synthesis of5-chloro-4-(((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-methoxy)-2-fluoro-N-sulfamoylbenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-2,4-difluoro-N-sulfamoylbenzamide andadamantan-1-ylmethanol with((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol, the titlecompound was obtained as a colorless solid (0.09 g, 15%): ¹H NMR (300MHz, DMSO-d₆) δ 11.73 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.58 (s, 2H),7.22 (d, J=12.4 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 2.49-2.38 (m, 1H),2.10-2.03 (m, 1H), 2.19-1.65 (m, 5H), 1.48-1.34 (m, 2H), 1.22 (s, 3H),0.86 (s, 3H); MS (ES−) m/z 403.2, 405.2 (M−1).

Example 79 Synthesis of5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with spiro[5.5]undecan-3-ol, the title compoundwas obtained as a colorless solid (0.03 g, 7%). ¹H NMR (300 MHz,DMSO-d₆) δ 11.73 (s, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.29 (d, J=12.6 Hz,1H), 4.68-4.60 (m, 1H), 2.86 (s, 6H), 1.84-1.74 (m, 2H), 1.66-1.51 (m,4H), 1.39-1.21 (m, 12H); MS (ES−) m/z 445.2, 447.2 (M−1).

Example 80 Synthesis of5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-(spiro[4.5]decan-8-yloxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with spiro[4.5]decan-8-ol, the title compound wasobtained as a colorless solid (0.06 g, 14%). ¹H NMR (300 MHz, DMSO-d₆) δ11.73 (s, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.31 (d, J=12.6 Hz, 1H),4.68-4.61 (m, 1H), 2.87 (s, 6H), 1.88-1.77 (m, 2H), 1.65-1.51 (m, 8H),1.44-1.32 (m, 6H); MS (ES−) m/z 431.2, 433.2 (M−1).

Example 81 Synthesis of5-chloro-4-(2-cyclobutylethoxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 2-cyclobutylethanol, the title compound wasobtained as a colorless solid (0.12 g, 32%): ¹H NMR (300 MHz, DMSO-d₆) δ11.77 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.22 (d, J=12.4 Hz, 1H), 4.08 (t,J=6.3 Hz, 2H), 2.87 (s, 6H), 2.47-2.40 (m, 1H), 2.10-1.99 (m, 2H),1.89-1.63 (m, 6H); MS (ES−) m/z 377.2, 379.2 (M−1).

Example 82 Synthesis of5-chloro-4-(3-cyclohexylpropoxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 3-cyclohexylpropan-1-ol, the title compoundwas obtained as a colorless solid (0.03 g, 7%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.75 (s, 1H), 7.72 (d, J=7.3 Hz, 1H), 7.23 (d, J=12.3 Hz,1H), 4.12 (t, J=6.2 Hz, 2H), 2.87 (s, 6H), 1.80-1.58 (m, 7H), 1.35-1.11(m, 6H), 0.94-0.88 (m, 2H); MS (ES−) m/z 419.2, 421.2 (M−1).

Example 83 Synthesis oftrans-5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-((4-(trifluoromethyl)cyclohexyl)oxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 4-(trifluoromethyl)cyclohexanol, the titlecompound was obtained as a colorless solid (0.02 g, 19%): ¹H NMR (300MHz, DMSO-d₆) δ 11.75 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.40 (d, J=12.6Hz, 1H), 4.61-4.53 (m, 1H), 2.87 (s, 6H), 2.45-2.32 (m, 1H), 2.18-2.10(m, 2H), 1.97-1.89 (m, 2H), 1.55-1.44 (m, 4H); MS (ES−) m/z 445.1, 447.1(M−1).

Example 84 Synthesis ofcis-5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-((4-(trifluoromethyl)-cyclohexyl)oxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 4-(trifluoromethyl)cyclohexanol, the titlecompound was obtained as a colorless solid (0.02 g, 19%): ¹H NMR (300MHz, DMSO-d₆) δ 11.75 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.35 (d, J=12.5Hz, 1H), 4.94 (s, 1H), 2.87 (s, 6H), 2.46-2.35 (m, 1H), 2.03-1.93 (m,2H), 1.72-1.53 (m, 6H); MS (ES−) m/z 445.2, 447.2 (M−1).

Example 85 Synthesis of5-chloro-4-(2-cycloheptylethoxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 2-cycloheptylethanol, the title compound wasobtained as a colorless solid (0.11 g, 26%): ¹H NMR (300 MHz, DMSO-d₆) δ11.75 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.4 Hz, 1H), 4.16 (t,J=6.2 Hz, 2H), 2.87 (s, 6H), 1.76-1.35 (m, 13H), 1.29-1.17 (m, 2H); MS(ES−) m/z 419.1, 421.1 (M−1).

Example 86 Synthesis of5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-((3-fluoroadamantan-1-yl)methoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N— (N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 3-fluoroadamantan-1-yl methanol, the titlecompound was obtained as a colorless solid (0.16 g, 35%): ¹H NMR (300MHz, DMSO-d₆) δ 11.77 (s, 1H), 7.73 (d, J=7.4 Hz, 1H), 7.23 (d, J=12.3Hz, 1H), 3.84 (s, 2H), 2.87 (s, 6H), 2.30 (br s, 2H), 1.87-1.76 (m, 6H),1.61-1.52 (m, 6H); MS (ES−) m/z 461.1, 463.1 (M−1).

Example 87 Synthesis of4-(2-(adamantan-1-yl)ethoxy)-5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with adamantan-1-ylethanol, the title compoundwas obtained as a colorless solid (0.15 g, 33%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.75 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.28 (d, J=12.5 Hz,1H), 4.18 (t, J=7.0 Hz, 2H), 2.87 (s, 6H), 1.93-1.88 (br s, 3H),1.70-1.54 (m, 14H); MS (ES−) m/z 457.2, 459.2 (M−1).

Example 90 Synthesis of5-chloro-4-(3-cyclopentylpropoxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 3-cyclopentylpropan-1-ol, the title compoundwas obtained as a colorless solid (0.22 g, 54%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.75 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.23 (d, J=12.4 Hz,1H), 4.14 (t, J=6.4 Hz, 2H), 2.87 (s, 6H), 1.86-1.70 (m, 5H), 1.64-1.40(m, 6H), 1.14-1.02 (m, 2H); MS (ES−) m/z 405.2, 407.2 (M−1).

Example 91 Synthesis of5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-((4-pentylbicyclo[2.2.2]octan-1-yl)-methoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with (4-pentylbicyclo[2.2.2]octan-1-yl)methanol,the title compound was obtained as a colorless solid (0.25 g, 51%): ¹HNMR (300 MHz, DMSO-d₆) δ 11.75 (s, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.19 (d,J=12.4 Hz, 1H), 3.76 (s, 2H), 2.87 (s, 6H), 1.53-1.48 (m, 6H), 1.38-1.06(m, 14H), 0.85 (t, J=7.0 Hz, 3H); MS (ES−) m/z 487.2, 489.2 (M−1).

Example 92 Synthesis of5-chloro-4-((3-chloroadamantan-1-yl)methoxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 3-chloroadamantan-1-yl methanol, the titlecompound was obtained as a colorless solid (0.15 g, 31%): ¹H NMR (300MHz, DMSO-d₆) δ 11.77 (s, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.23 (d, J=12.3Hz, 1H), 3.82 (s, 2H), 2.87 (s, 6H), 2.22 (br s, 2H), 2.14-2.02 (m, 6H),1.70-1.55 (s, 6H); MS (ES−) m/z 477.1, 479.1 (M−1).

Example 93 Synthesis of5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-((1-fluorocyclohexyl)-methoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with (1-fluorocyclohexyl)methanol, the titlecompound was obtained as a colorless solid (0.08 g, 19%): ¹H NMR (300MHz, DMSO-d₆) δ 11.79 (s, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.30 (d, J=12.3Hz, 1H), 4.24 (d, J=21.2 Hz, 2H), 2.88 (s, 6H), 1.96-1.87 (m, 2H),1.72-1.50 (m, 7H), 1.37-1.24 (m, 1H); MS (ES−) m/z 409.1, 411.1 (M−1).

Example 94 Synthesis of-chloro-2-fluoro-N-(methylsulfonyl)-4-((1-(trifluoromethyl)cyclobutyl)-methoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with(1-(trifluoromethyl)cyclobutyl)methanol, the title compound was obtainedas a colorless solid (0.05 g, 12%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.11(s, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.39 (d, J=12.4 Hz, 1H), 4.41 (s, 2H),3.35 (s, 3H), 2.39-2.26 (m, 2H), 2.19-2.09 (m, 3H), 2.01-1.90 (m, 1H);MS (ES−) m/z 402.1, 404.1 (M−1).

Example 95 Synthesis of5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-((1-(trifluoromethyl)-cyclobutyl)methoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with (1-(trifluoromethyl)cyclobutyl)methanol, thetitle compound was obtained as a colorless solid (0.05 g, 12%): ¹H NMR(300 MHz, DMSO-d₆) δ 11.82 (s, 1H), 7.76 (d, J=7.4 Hz, 1H), 7.38 (d,J=12.2 Hz, 1H), 4.41 (s, 2H), 2.88 (s, 6H), 2.38-2.26 (m, 2H), 2.19-2.08(m, 3H), 2.02-1.91 (m, 1H); MS (ES−) m/z 431.1, 433.1 (M−1).

Example 96 Synthesis of5-chloro-4-((2,2-dimethylchroman-6-yloxy)methyl)-2-fluoro-N-(N-methylsulfamoyl)benzamide

The synthetic procedure was the same as Example 74. LCMS (ESI) Method A:RT=5.20 min, m/z: 468.7 [M+H]⁺; ¹H-NMR (500 MHz, DMSO-d₆) 11.95 (s, 1H),7.76 (d, J=6.0 Hz, 1H), 7.51 (s, 1H), 6.80-6.75 (m, 2H), 6.63 (d, J=9.0Hz, 1H), 5.08 (s, 2H), 2.71 (t, J=6.5 Hz, 2H), 2.54 (s, 3H), 1.96-1.98(m, 1H), 1.72 (t, J=6.5 Hz, 2H), 1.24 (s, 6H).

Example 97 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-4-((2,2-dimethylchroman-6-yloxy)methyl)-2-fluorobenzamide

The synthetic procedure was the same as Example 74. LCMS (ESI) Method A:RT=5.48 min, m/z: 483.2 [M+H]⁺; ¹H-NMR (500 MHz, MeOD-d₄) δ 7.66 (d,J=6.0 Hz, 1H), 7.38 (d, J=10.5 Hz, 1H), 6.66-6.64 (m, 2H), 6.54 (d,J=9.0 Hz, 1H), 5.02 (s, 2H), 4.08-4.05 (m, 4H), 2.67 (t, J=6.5 Hz, 2H),2.19-2.16 (m, 2H), 1.68 (t, J=6.5 Hz, 2H), 1.19 (s, 6H).

Example 98 Synthesis of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N-(morpholinosulfonyl)-benzamide

To a mixture of 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid(0.17 g, 0.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.22g, 1.15 mmol) and 4-dimethylaminopyridine (0.14 g, 1.15 mmol) inanhydrous dichloromethane (10 mL) was added morpholine-4-sulfonamide(0.17 g, 1.0 mmol) at ambient temperature. The resulting mixture wasstirred at ambient temperature for 16 h. The mixture was quenched withhydrochloride acid (1N, 30 mL) followed by extraction with ethyl acetate(100 mL). The organic layer was washed with water (30 mL), dried overanhydrous sodium sulfate, and filtered. The filtrate was concentrated invacuo, the residue was purified by silica gel column chromatographyusing 10-60% gradient ethyl acetate (containing 0.2% acetic acid) inhexanes to afford the title compound as an off-white solid (0.05 g,20%): ¹H NMR (300 MHz, DMSO-d₆) δ 7.88 (s, 1H), 6.88 (s, 1H), 4.06 (d,J=6.8 Hz, 2H), 3.39 (s, 3H), 2.50-2.42 (m, 1H), 2.12-2.05 (m, 1H),1.98-1.94 (m, 1H), 1.90-1.68 (m, 4H), 1.50-1.41 (m, 2H), 1.22 (s, 3H),0.87 (s, 3H); MS (ES−) m/z 397.2, 399.2 (M−1); MS (ES+) m/z 399.1, 401.1(M+1);

Example 99 Synthesis ofN-((1H-imidazol-4-yl)sulfonyl)-4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzamide

Following the procedure as described in Example 98 and making variationsas required to replace morpholine-4-sulfonamide with1H-imidazole-4-sulfonamide, the title compound was obtained as acolorless solid (0.07 g, 15%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.72 (s,2H), 7.94-7.88 (m, 2H), 7.64 (d, J=7.5 Hz, 1H), 7.15 (d, J=12.4 Hz, 1H),3.70 (s, 2H), 1.99 (br s, 3H), 1.74-1.63 (m, 12H); MS (ES−) m/z 466.2,468.2 (M−1).

Example 100 Synthesis of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N-(N-methylsulfamoyl)benzamide

Following the procedure as described in Example 98 and making variationsas required to replace morpholine-4-sulfonamide with N-methylsulfamide,the title compound was obtained as a colorless solid (0.07 g, 34%): ¹HNMR (300 MHz, DMSO-d₆) δ 11.68 (s, 1H), 7.72-7.66 (m, 2H), 7.22 (d,J=12.4 Hz, 1H), 3.72 (s, 2H), 2.55 (d, J=4.8 Hz, 3H), 1.99 (br s, 3H),1.75-1.64 (m, 12H); MS (ES−) m/z 429.3, 431.3 (M−1); MS (ES+) m/z 431.2,433.2 (M+1);

Example 101 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluorobenzamide

Following the procedure as described in Example 98 and making variationsas required to replace morpholine-4-sulfonamide withazetidine-1-sulfonamide, the title compound was obtained as a colorlesssolid (0.08 g, 36%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.81 (s, 1H), 7.77 (d,J=7.5 Hz, 1H), 7.24 (d, J=12.4 Hz, 1H), 4.05 (t, J=7.7 Hz, 4H), 3.73 (s,2H), 2.22-2.12 (m, 2H), 1.99 (br s, 3H), 1.75-1.64 (m, 12H); MS (ES−)m/z 455.3, 457.3 (M−1); MS (ES+) m/z 457.2, 459.2 (M+1).

Example 102 Synthesis of4-(adamantan-1-ylmethoxy)-N-(methylsulfonyl)-3-(trifluoromethyl)benzamide

Following the procedure as described in Example 98 and making variationsas required to replace4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-3-(trifluoromethyl)benzoic acid andmorpholine-4-sulfonamide with methanesulfonamide, the title compound wasobtained as a colorless solid (0.11 g, 51%): ¹H NMR (300 MHz, DMSO-d₆) δ12.22 (s, 1H), 8.25-8.19 (m, 2H), 7.37 (d, J=8.8 Hz, 1H), 3.77 (s, 2H),3.37 (s, 3H), 1.99 (br s, 3H), 1.75-1.63 (m, 12H); MS (ES−) m/z 430.3(M−1); MS (ES+) m/z 432.2 (M+1).

Example 103 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-3-(trifluoromethyl)benzamide

Following the procedure as described in Example 98 and making variationsas required to replace4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-3-(trifluoromethyl)benzoic acid andmorpholine-4-sulfonamide with azetidine-1-sulfonamide, the titlecompound was obtained as a colorless solid (0.05 g, 22%): ¹H NMR (300MHz, DMSO-d₆) δ 11.92 (s, 1H), 8.26-8.22 (m, 2H), 7.38-7.35 (m, 1H),4.05 (t, J=7.7 Hz, 4H), 3.76 (s, 2H), 2.20-2.09 (m, 2H), 1.99 (br s,3H), 1.75-1.63 (m, 12H); MS (ES−) m/z 471.3 (M−1); MS (ES+) m/z 473.2(M+1).

Example 104 Synthesis of5-chloro-2-fluoro-4-((3-(5-methyl-2H-tetrazol-2-yl)adamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with(3-(5-methyl-2H-tetrazol-2-yl)-adamantan-1-yl)methanol, the titlecompound was obtained as a colorless solid (0.07 g, 33%): ¹H NMR (300MHz, DMSO-d₆) δ 12.11 (s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.25 (d, J=12.4Hz, 1H), 3.90 (s, 2H), 3.34 (s, 3H), 2.45 (s, 3H), 2.35-2.07 (m, 8H),1.80-1.66 (m, 6H); MS (ES−) m/z 496.3, 498.3 (M−1); MS (ES+) m/z 498.2,500.2 (M+1).

Example 105 Synthesis of5-chloro-4-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with((1R,2R,5R)-6,6-dimethylbicyclo-[3.1.1]heptan-2-yl)methanol, the titlecompound was obtained as a colorless solid (0.16 g, 32%): ¹H NMR (300MHz, DMSO-d₆) δ 12.09 (s, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.25 (d, J=12.5Hz, 1H), 3.96 (d, J=6.8 Hz, 1H), 3.35 (s, 3H), 2.45-2.38 (m, 1H),2.10-2.03 (m, 1H), 1.94-1.65 (m, 5H), 1.48-1.37 (m, 2H), 1.21 (s, 3H),0.85 (s, 3H); MS (ES−) m/z 402.3, 404.3 (M−1); MS (ES+) m/z 404.2, 406.2(M+1).

Example 106 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-hydroxyazetidin-1-yl)sulfonyl)benzamide

Step 1. Preparation of4-(adamantan-1-ylmethoxy)-N-((3-((tert-butyldiphenylsilyl)-oxy)azetidin-1-yl)sulfonyl)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace methanesulfonamide with3-((tert-butyl-diphenylsilyl)oxy)azetidine-1-sulfonamide, the titlecompound was obtained as colorless solid (0.29 g, 40%): MS (ES+) m/z717.3 (M+1); MS (ES−) m/z 715.4 (M−1).

Step 2. Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-hydroxyazetidin-1-yl)sulfonyl)benzamide

To a solution of4-(adamantan-1-ylmethoxy)-N-((3-((tert-butyldiphenylsilyl)-oxy)azetidin-1-yl)sulfonyl)-5-cyclopropyl-2-fluorobenzamide(0.28 g, 0.39 mmol) in anhydrous dichloromethane (10 mL) was addedtetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 1.6 mL,1.56 mmol) at ambient temperature. The reaction mixture was stirred atambient temperature for 2 h. The mixture was quenched with aqueoushydrochloride acid solution (1N, 30 mL) followed by extraction withethyl acetate (100 mL). The organic layer was washed with water (30 mL),dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated in vacuo, the residue was purified by silica gel columnchromatography using 10%-100% gradient ethyl acetate (containing 0.2%acetic acid) in hexanes to afford the title compound as an off-whitesolid (0.07 g, 36%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.62 (s, 1H), 7.15 (d,J=8.3 Hz, 1H), 6.93 (d, J=13.0 Hz, 1H), 5.83 (d, J=6.0 Hz, 1H),4.45-4.35 (m, 1H), 4.14-4.09 (m, 2H), 3.89-3.84 (m, 2H), 3.65 (s, 2H),2.09-1.99 (m, 4H), 1.75-1.67 (m, 12H), 0.94-0.88 (m, 2H), 0.69-0.66 (m,2H); MS (ES+) m/z 479.3 (M+1); MS (ES−) m/z 477.4 (M−1).

Example 107 Synthesis of4-(adamantan-1-ylmethoxy)-5-ethyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of tert-butyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-vinylbenzoate

A mixture of tert-butyl4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoate (2.00 g, 5.06 mmol),vinylboronic acid pinacol ester (1.56 g, 10.1 mmol) and sodium carbonate(1.61 g, 15.2 mmol) in dioxane (20 mL) and water (5 mL) was bubbled witha nitrogen atmosphere for 10 min, tributylphosphine tetrafluoroborate(0.15 g, 0.51 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.023 g,0.025 mmol) was added to this reaction mixture. The reaction mixture washeated to 100° C. for 24 h and then cooled to ambient temperature. Water(50 mL) was added and the mixture extracted with ethyl acetate (100mL×3), the combined organics were washed with brine; dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified over column chromatography, eluting with 30% dichloromethane inhexanes to give the crude product, which was used for next step withoutfurther purification: MS (ES+) m/z 398.3 (M+1).

Step 2. Preparation of 4-(adamantan-1-ylmethoxy)-2-fluoro-5-vinylbenzoicacid

To a solution of tert-butyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-vinylbenzoate (2.4 g, 6.2 mmol) indichloromethane (10 mL), was added trifluoroacetic acid (10 ml). Thereaction mixture was stirred at ambient temperature for 16 h and thenconcentrated in vacuo. The residue was triturated in hexanes (50 mL),the solid was filtered and dried to give the title compound as a lightyellow solid (1.5 g, 73% in 2 steps): ¹H NMR (300 MHz, DMSO-d₆) δ 12.94(br s, 1H), 7.92 (d, J=8.6 Hz, 1H), 6.96-6.81 (m, 2H), 5.84-5.78 (m,1H), 5.32-5.28 (m, 1H), 3.62 (s, 2H), 3.34 (s, 3H), 1.95 (s, 3H),1.70-1.60 (m, 12H); MS (ES+) m/z 331.2 (M+1); MS (ES−) m/z 329.4 (M−1).

Step 3. Preparation of 4-(adamantan-1-ylmethoxy)-5-ethyl-2-fluorobenzoicacid

A mixture of 4-(adamantan-1-ylmethoxy)-2-fluoro-5-vinylbenzoic acid(1.00 g, 3.03 mmol) and 10% palladium on activated carbon (0.10 g) inethyl acetate (150 mL) was fitted with a hydrogen balloon. The reactionmixture was stirred at ambient temperature for 42 h. The mixture wasfiltered through a pad of diatomaceous earth, and washed with ethylacetate (50 mL). The filtrate was concentrated in vacuo, the residue wasrecrystallized from ethyl acetate and hexanes to afford the titlecompound as an off-white solid (0.75 g, 74%): ¹H NMR (300 MHz, DMSO-d₆)δ 12.80 (br s, 1H), 7.63 (d, J=8.6 Hz, 1H), 6.87 (d, J=13.2 Hz, 1H),3.61 (s, 2H), 5.57 (d, J=7.5 Hz, 2H), 1.99 (s, 3H), 1.75-1.63 (m, 12H),1.14 (t, J=7.5 Hz, 3H); MS (ES+) m/z 333.2 (M+1).

Step 4. Preparation of4-(adamantan-1-ylmethoxy)-5-ethyl-2-fluoro-N-(methylsulfonyl)-benzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-5-ethyl-2-fluorobenzoic acid, the titlecompound was obtained as colorless solid (0.17 g, 69%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.87 (s, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.94 (d, J=13.1 Hz,1H), 3.62 (s, 2H), 3.34 (s, 3H), 2.58 (q, J=7.5 Hz, 2H), 1.99 (br s,3H), 1.75-1.64 (m, 12H), 1.15 (t, J=7.5 Hz, 3H); MS (ES+) m/z 410.2(M+1); MS (ES−) m/z 408.3 (M−1).

Example 108 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-ethyl-2-fluorobenzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-5-ethyl-2-fluorobenzoic acid andmethanesulfonamide with azetidine-1-sulfonamide, the title compound wasobtained as colorless solid (0.16 g, 59%): ¹H NMR (300 MHz, DMSO-d₆) δ11.60 (s, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.94 (d, J=13.0 Hz, 1H),4.08-4.01 (m, 4H), 3.62 (s, 2H), 2.59 (q, J=7.5 Hz, 2H), 2.22-2.12 (m,2H), 1.99 (br s, 3H), 1.75-1.64 (m, 12H), 1.15 (t, J=7.5 Hz, 3H); MS(ES+) m/z 451.2 (M+1); MS (ES−) m/z 449.3 (M−1).

Example 109 Synthesis of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N-((3-fluoroazetidin-1-yl)-sulfonyl)benzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid andmethanesulfonamide with 3-fluoroazetidine-1-sulfonamide, the titlecompound was obtained as colorless solid (0.15 g, 52%): ¹H NMR (300 MHz,DMSO-d₆) δ 12.02 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.25 (d, J=12.4 Hz,1H), 5.49-5.43 (m, 0.5H), 5.30-5.24 (m, 0.5H), 4.45-4.32 (m, 2H),4.26-4.13 (m, 2H), 3.73 (s, 2H), 1.99 (br s, 3H), 1.75-1.64 (m, 12H); MS(ES+) m/z 475.1, 477.1 (M+1); MS (ES−) m/z 473.2, 475.2 (M−1).

Example 110 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace methanesulfonamide with3-fluoroazetidine-1-sulfonamide, the title compound was obtained ascolorless solid (0.23 g, 80%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.80 (s,1H), 7.15 (d, J=8.3 Hz, 1H), 6.95 (d, J=13.0 Hz, 1H), 5.48-5.42 (m,0.5H), 5.29-5.23 (m, 0.5H), 4.43-4.30 (m, 2H), 4.25-4.12 (m, 2H), 3.65(s, 2H), 2.08-1.99 (m, 4H), 1.75-1.67 (m, 12H), 0.94-0.88 (m, 2H),0.70-0.65 (m, 2H); MS (ES+) m/z 481.2 (M+1); MS (ES−) m/z 479.3 (M−1).

Example 111 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace methanesulfonamide withcyclopropanesulfonamide, the title compound was obtained as colorlesssolid (0.19 g, 71%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.80 (s, 1H), 7.14 (d,J=8.3 Hz, 1H), 6.93 (d, J=13.1 Hz, 1H), 3.65 (s, 2H), 3.12-3.03 (m, 1H),2.07-1.99 (m, 4H), 1.75-1.66 (m, 12H), 1.13-1.10 (m, 4H), 0.94-0.88 (m,2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 448.2 (M+1); MS (ES−) m/z 446.3(M−1).

Example 112 Synthesis of4-(adamantan-1-ylmethoxy)-5-chloro-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid andmethanesulfonamide with cyclopropanesulfonamide, the title compound wasobtained as colorless solid (0.13 g, 49%): ¹H NMR (300 MHz, DMSO-d₆) δ12.03 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.24 (d, J=12.5 Hz, 1H), 3.73 (s,2H), 3.12-3.03 (m, 1H), 1.99 (s, 3H), 1.75-1.64 (m, 12H), 1.15-1.11 (m,4H); MS (ES+) m/z 442.1, 444.1 (M+1); MS (ES−) m/z 440.2, 442.2 (M−1).

Example 113 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace methanesulfonamide withpyrrolidine-1-sulfonamide, the title compound was obtained as colorlesssolid (0.17 g, 85%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.53 (s, 1H), 7.10 (d,J=8.3 Hz, 1H), 6.91 (d, J=13.0 Hz, 1H), 3.63 (s, 2H), 3.42-3.37 (m, 4H),2.05-1.99 (m, 4H), 1.84-1.67 (m, 16H), 0.93-0.87 (m, 2H), 0.69-0.64 (m,2H); MS (ES+) m/z 477.3 (M+1); MS (ES−) m/z 475.3 (M−1).

Example 114 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-((3,3-difluoroazetidin-1-yl)sulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace methanesulfonamide with3,3-difluoroazetidine-1-sulfonamide, the title compound was obtained ascolorless solid (0.20 g, 80%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.01 (s,1H), 7.16 (d, J=8.3 Hz, 1H), 6.96 (d, J=13.0 Hz, 1H), 4.58 (t, J=12.8Hz, 4H), 3.65 (s, 2H), 2.08-1.99 (m, 4H), 1.75-1.67 (m, 12H), 0.95-0.88(m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 499.2 (M+1); MS (ES−) m/z 497.3(M−1).

Example 115 Synthesis of4-(adamantan-1-ylmethoxy)-N-(tert-butylsulfonyl)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace methanesulfonamide withtert-butylsulfonamide, the title compound was obtained as colorlesssolid (0.17 g, 73%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.41 (s, 1H), 7.06 (d,J=8.2 Hz, 1H), 6.91 (d, J=12.8 Hz, 1H), 3.63 (s, 2H), 2.06-1.99 (m, 4H),1.75-1.66 (m, 12H), 1.38 (s, 9H), 0.93-0.87 (m, 2H), 0.68-0.63 (m, 2H);MS (ES+) m/z 464.2 (M+1); MS (ES−) m/z 462.2 (M−1).

Example 116 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-(ethylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace methanesulfonamide withethanesulfonamide, the title compound was obtained as colorless solid(0.17 g, 79%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.78 (s, 1H), 7.14 (d, J=8.3Hz, 1H), 6.93 (d, J=13.1 Hz, 1H), 3.64 (s, 2H), 3.47 (q, J=7.3 Hz, 2H),2.06-1.99 (m, 4H), 1.75-1.66 (m, 12H), 1.24 (t, J=7.3 Hz, 3H), 1.38 (s,9H), 0.94-0.87 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 436.2 (M+1); MS(ES−) m/z 434.3 (M−1).

Example 117 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(N-(2-methoxyethyl)sulfamoyl)benzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace methanesulfonamide with2-methoxyethyl-sulfamoylamine, the title compound was obtained ascolorless solid (0.24 g, 53%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.53 (s,1H), 7.76 (t, J=5.8 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.91 (d, J=13.0 Hz,1H), 4.45 (t, J=5.0 Hz, 1H), 3.63 (s, 2H), 3.39 (t, J=6.0 Hz, 2H), 3.19(s, 3H), 3.12-3.06 (m, 2H), 2.08-1.99 (m, 4H), 1.75-1.66 (m, 12H),0.94-0.87 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 481.2 (M+1); MS (ES−)m/z 479.3 (M−1).

Example 118 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-methoxyazetidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace methanesulfonamide with3-methoxyazetidine-1-sulfonamide, the title compound was obtained ascolorless solid (0.22 g, 76%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.69 (s,1H), 7.13 (d, J=8.3 Hz, 1H), 6.93 (d, J=13.0 Hz, 1H), 4.21-4.13 (m, 3H),3.95-3.93 (m, 2H), 3.65 (s, 2H), 3.17 (s, 3H), 2.08-1.99 (m, 4H),1.75-1.67 (m, 12H), 0.94-0.87 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z493.3 (M+1); MS (ES−) m/z 491.4 (M−1).

Example 119 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(morpholinosulfonyl)benzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace methanesulfonamide withmorpholine-4-sulfonamide, the title compound was obtained as colorlesssolid (0.15 g, 59%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.71 (s, 1H), 7.12 (d,J=8.3 Hz, 1H), 6.92 (d, J=13.0 Hz, 1H), 3.65-3.62 (m, 4H), 3.27-3.24 (m,4H), 2.06-1.99 (m, 4H), 1.75-1.66 (m, 12H), 0.93-0.87 (m, 2H), 0.70-0.64(m, 2H); MS (ES+) m/z 493.2 (M+1); MS (ES−) m/z 491.3 (M−1).

Example 120 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)-sulfonyl)benzamide

Following the procedure as described in preparation of Example 50 step 5and making variation as required to replace methanesulfonamide with2-methoxyethane-1-sulfonamide, the title compound was obtained as acolorless solid (0.46 g, 68%): ¹H NMR (300 MHz, CDCl₃) δ 8.71-8.60 (m,1H), 7.63-7.53 (m, 1H), 6.61-6.50 (m, 1H), 3.91-3.74 (m, 4H), 3.56 (s,2H), 3.31 (s, 3H), 2.08-2.01 (m, 4H), 1.83-1.64 (m, 12H), 0.99-0.89 (m,2H), 0.70-0.61 (m, 2H); MS (ES+) m/z 466.3 (M+1).

Example 121 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-hydroxyethyl)-sulfonyl)benzamide

To a cooled (0° C.) stirred solution of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide(0.30 g, 0.64 mmol) in methylene chloride (6 mL) was added a solution ofboron tribromide (0.12 mL, 1.29 mmol) and 2,6-lutidine (0.15 mL, 1.29mmol) in methylene chloride (1 mL) dropwise. The reaction mixture wasstirred at 0° C. for 2 h and at ambient temperature for 1 h, then cooledto 0° C. and quenched with saturated sodium bicarbonate solution (15mL). The mixture was diluted with methylene chloride (15 mL), layerswere separated, and the aqueous layer was extracted with methylenechloride (2×15 mL). The combined organic layers were washed with brine(20 mL), dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyeluting with a 10% to 75% gradient of ethyl acetate in hexanes to affordthe title compound as colorless solid (0.07 g, 25%): ¹H NMR (300 MHz,CDCl₃) δ 8.71 (br. s, 1H), 7.64-7.52 (m, 1H), 6.64-6.50 (m, 1H),4.22-4.07 (m, 2H), 3.86-3.74 (m, 2H), 3.56 (s, 2H), 2.57 (s, 1H),2.09-1.99 (m, 4H), 1.84-1.63 (m, 12H), 1.00-0.89 (m, 2H), 0.69-0.59 (m,2H); MS (ES+) m/z 452.3 (M+1).

Example 122 Synthesis of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N-((2-methoxyethyl)-sulfonyl)benzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid andmethanesulfonamide with 2-methoxyethane-1-sulfonamide, the titlecompound was obtained as a colorless solid (0.05 g, 9%): ¹H NMR (300MHz, CDCl₃) δ 8.68-8.54 (m, 1H), 8.13-8.03 (m, 1H), 6.74-6.62 (m, 1H),3.91-3.74 (m, 4H), 3.59 (s, 2H), 3.31 (s, 3H), 2.05 (s, 3H), 1.85-1.64(m, 12H); MS (ES−) m/z 458.3 (M−1), 460.3 (M−1).

Example 123 Synthesis of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N-((2-hydroxyethyl)-sulfonyl)benzamide

Following the procedure as described in Example 121 and making variationas required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamidewith4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide,the title compound was obtained as a colorless solid (0.04 g, 15%): ¹HNMR (300 MHz, CDCl₃) δ 8.74-8.61 (m, 1H), 8.11-8.03 (m, 1H), 6.75-6.64(m, 1H), 4.23-4.08 (m, 2H), 3.86-3.76 (m, 2H), 3.59 (s, 2H), 2.50-2.40(m, 1H), 2.12-1.96 (m, 3H), 1.86-1.62 (m, 12H); MS (ES−) m/z 444.3(M−1), 446.3 (M−1);

Example 124 Synthesis of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N—(((S)-3-hydroxypyrrolidin-1-yl)sulfonyl)benzamide

Step 1. Preparation of(S)-3-((4-methoxybenzyl)oxy)pyrrolidine-1-sulfonamide

A mixture of (S)-3-((4-methoxybenzyl)oxy)pyrrolidine (4.50 g, 21.7 mmol)and sulfamide (2.50 g, 26.0 mmol) in dimethoxyethane (100 mL) wasrefluxed for 72 h. The reaction was concentrated in vacuo. Purificationof the residue by column chromatography (30% to 100% gradient ethylacetate in hexanes) afforded the title compound as a colorless solid(3.80 g, 61%): ¹H NMR (300 MHz, DMSO-d₆) δ 7.27-7.24 (m, 2H), 6.91-6.88(m, 2H), 6.74 (s, 2H), 4.39 (s, 2H), 4.16-4.11 (m, 1H), 3.74 (s, 3H),3.30-3.25 (m, 1H), 3.18-3.10 (m, 3H), 2.00-1.88 (m, 2H); MS (ES+) m/z287.2 (M+1); MS (ES−) m/z 285.3 (M−1).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N—(((S)-3-((4-methoxybenzyl)oxy)pyrrolidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid andmethanesulfonamide with(S)-3-((4-methoxybenzyl)oxy)pyrrolidine-1-sulfonamide, the titlecompound was obtained as colorless solid (0.17 g, 47%): MS (ES+) m/z607.1, 609.1 (M+1); MS (ES−) m/z 605.3, 607.3 (M−1).

Step 3. Preparation of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N—(((S)-3-hydroxypyrrolidin-1-yl)sulfonyl)benzamide

A mixture of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N—(((S)-3-((4-methoxybenzyl)oxy)pyrrolidin-1-yl)sulfonyl)benzamide(0.17 g, 0.28 mmol) in dichloromethane (18 mL) and water (2 mL) wasadded 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.08 g, 0.36 mmol) atambient temperature and stirred for 16 h. Water (20 mL) was added andthe mixture extracted with ethyl acetate (80 mL×2), the combinedorganics were washed with brine; dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was filtered through a short silicongel column, eluted with 5%-60% gradient ethyl acetate in hexanes to givethe title compound as colorless solid (0.08 g, 55%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.73 (s, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.21 (d, J=12.4 Hz,1H), 5.07 (brs, 1H), 4.32-4.27 (m, 1H), 3.71 (s, 2H), 3.56-3.48 (m, 3H),3.23-3.19 (m, 1H), 1.99 (s, 3H), 1.93-1.63 (m, 14H); MS (ES+) m/z 487.2,489.1 (M+1); MS (ES−) m/z 485.3, 487.3 (M−1).

Example 125 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N—(((S)-3-hydroxypyrrolidin-1-yl)sulfonyl)benzamide

Step 1. Preparation of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N—(((S)-3-((4-methoxybenzyl)oxy)pyrrolidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace methanesulfonamide with(S)-3-((4-methoxybenzyl)-oxy)pyrrolidine-1-sulfonamide, the titlecompound was obtained as colorless solid (0.31 g, 84%): MS (ES+) m/z613.2 (M+1); MS (ES−) m/z 611.3 (M−1).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N—(((S)-3-hydroxypyrrolidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 124 step 3 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid, the titlecompound was obtained as off-white solid (0.04 g, 17%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.51 (s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.90 (d, J=12.9 Hz,1H), 5.07 (br s, 1H), 4.32-4.27 (m, 1H), 3.63 (s, 2H), 3.55-3.48 (m,3H), 3.20-3.16 (m, 1H), 2.07-1.99 (m, 4H), 1.93-1.63 (m, 14H), 0.93-0.87(m, 2H), 0.69-0.63 (m, 2H); MS (ES+) m/z 493.2 (M+1); MS (ES−) m/z 491.3(M−1).

Example 126 Synthesis of5-cyclopropyl-2-fluoro-4-((3-methoxyadamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 49 and making variationsas required to replace4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)-benzamidewith5-chloro-2-fluoro-4-((3-methoxyadamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamide,the title compound was obtained as colorless solid (0.06 g, 42%): ¹H NMR(300 MHz, DMSO-d₆) δ 11.89 (s, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.93 (d,J=13.1 Hz, 1H), 3.73 (s, 2H), 3.34 (s, 3H), 3.12 (s, 3H), 2.21 (s, 2H),2.07-1.98 (m, 1H), 1.70-1.56 (m, 12H), 0.94-0.88 (m, 2H), 0.70-0.65 (m,2H); MS (ES+) m/z 452.2 (M+1); MS (ES−) m/z 450.3 (M−1).

Example 127 Synthesis of5-cyclopropyl-2-fluoro-4-((3-fluoroadamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamideand2-fluoro-4-((3-fluoroadamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 49 and making variationsas required to replace4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamidewith5-chloro-2-fluoro-4-((3-fluoroadamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamide,5-cyclopropyl-2-fluoro-4-((3-fluoroadamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamidewas obtained as colorless solid (0.09 g, 35%): ¹H NMR (300 MHz, DMSO-d₆)δ 11.90 (s, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.94 (d, J=13.0 Hz, 1H), 3.77(s, 2H), 3.34 (s, 3H), 2.30 (s, 2H), 2.07-1.98 (m, 1H), 1.83-1.78 (m,6H), 1.62-1.58 (m, 6H), 0.94-0.88 (m, 2H), 0.70-0.64 (m, 2H); MS (ES+)m/z 440.2 (M+1); MS (ES−) m/z 438.3 (M−1).2-fluoro-4-((3-fluoroadamantan-1-yl)methoxy)-N-(methylsulfonyl)benzamidewas also obtained as a colorless solid (0.02 g, 8%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.95 (s, 1H), 7.63 (t, J=8.7 Hz, 1H), 6.98-6.86 (m, 2H),3.75 (s, 2H), 3.33 (s, 3H), 2.28 (s, 2H), 1.82-1.73 (m, 6H), 1.61-1.54(m, 6H); MS (ES+) m/z 400.2 (M+1); MS (ES−) m/z 398.2 (M−1).

Example 128 Synthesis of4-(adamantan-1-ylmethoxy)-2-fluoro-5-methyl-N-(methylsulfonyl)benzamide

Step 1. Preparation of4-(adamantan-1-ylmethoxy)-2-fluoro-5-methylbenzoic acid

To a solution of 1-adamantane methanol (2.40 g, 14.40 mmol) in anhydrousdimethylsulfoxide (20 ml) was added potassium tert-butoxide (4.86 g,43.30 mmol) and the suspension was stirred at ambient temperature for 30min. 5-chloro-2,4-difluorobenzoic acid (2.50 g, 14.40 mmol) was added tothe reaction mixture and stirred at 50° C. for 72 h. The reactionmixture was acidified to pH=1 with cold aqueous hydrochloric acidsolution (1N), followed by addition of 25% aqueous ammonium chloridesolution (200 mL). The solid was collected by filtration and washed withwater and a mixture of hexanes/diethyl ether (3/1, v/v).Recrystallization of the crude product from ethyl acetate and hexanes toafford the title compound as a beige color solid (0.77 g, 17%): MS (ES+)m/z 437.2 (M+1).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-2-fluoro-5-methyl-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-2-fluoro-5-methylbenzoic acid, the titlecompound was obtained as colorless solid (0.06 g, 27%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.85 (s, 1H), 7.48 (d, J=8.3 Hz, 1H), 6.93 (d, J=13.0 Hz,1H), 3.62 (s, 2H), 3.33 (s, 3H), 2.15 (s, 3H), 1.99 (s, 3H), 1.75-1.66(m, 12H); MS (ES+) m/z 396.2 (M+1); MS (ES−) m/z 394.2 (M−1).

Example 129 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-methylbenzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-2-fluoro-5-methylbenzoic acid andmethanesulfonamide with azetidine-1-sulfonamide, the title compound wasobtained as colorless solid (0.06 g, 27%): ¹H NMR (300 MHz, DMSO-d₆) δ11.59 (s, 1H), 7.48 (d, J=8.3 Hz, 1H), 6.93 (d, J=12.9 Hz, 1H), 4.04 (t,J=7.7 Hz, 4H), 3.62 (s, 2H), 2.19-2.14 (m, 5H), 1.99 (s, 3H), 1.75-1.66(m, 12H); MS (ES+) m/z 437.2 (M+1); MS (ES−) m/z 435.2 (M−1).

Example 130 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(N-(3-hydroxypropyl)sulfamoyl)benzamide

To a stirred solution of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid (0.30 g,0.87 mmol) in dichloromethane (15 mL) were addedN-(3-dimethyl-aminopropyl)-N′-ethylcarbodiimide hydrochloride (0.38 g,2.00 mmol) and 4-(dimethylamino)pyridine (0.25 g, 2.00 mmol). Thereaction stirred at ambient temperature for 10 min,3-(sulfamoylamino)propyl 2,2,2-trifluoroacetate (0.50 g, 2.00 mmol) wasadded and stirring continued at ambient temperature for 72 h. sodiumcarbonate solution (3M, 10 mL) was added and stirred at ambienttemperature for 4 h, aqueous hydrochloric acid (3N) were added to pH=1and diluted with ethyl acetate (200 mL), washed with water and brine;dried over anhydrous sodium sulfate and concentrated in vacuo.Purification of the residue by reversed-phase column chromatographyafforded the title compound as colorless solid (0.11 g, 27%): ¹H NMR(300 MHz, DMSO-d₆) 11.50 (s, 1H), 7.66 (br s, 1H), 7.10 (d, J=8.3 Hz,1H), 6.90 (d, J=12.9 Hz, 1H), 4.45 (t, J=5.0 Hz, 1H), 3.63 (s, 2H),3.43-3.37 (m, 2H), 3.00-2.93 (m, 2H), 2.07-1.99 (m, 4H), 1.75-1.56 (m,14H), 0.93-0.87 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 481.2 (M+1); MS(ES−) m/z 479.3 (M−1).

Example 131 Synthesis of4-(adamantan-1-ylmethoxy)-3-cyclobutyl-N-(methylsulfonyl)benzamide

Step 1. Preparation of4-(adamantan-1-ylmethoxy)-3-(1-hydroxycyclobutyl)benzonitrile

To a cooled (0° C.) stirred solution of4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile (3.20 g, 9.24 mmol) intetrahydrofuran (40 mL) was added a solution of isopropylmagnesiumchloride lithium chloride complex in tetrahydrofuran (1.3 M, 15.0 mL,19.5 mmol) dropwise. The reaction mixture was stirred at 0° C. for 2 hand cyclobutanone (1.52 mL, 20.33 mmol) was added. Stirring wascontinued at 0° C. for 2 h and quenched with saturated ammonium chloridesolution (30 mL). The mixture was extracted with ethyl acetate (3×50mL). The combined organic layers were washed with brine (50 mL), driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo.The residue was purified by column chromatography eluting with a 10% to25% gradient of ethyl acetate in hexanes to afford4-(adamantan-1-ylmethoxy)-3-(1-hydroxycyclobutyl)benzonitrile ascolorless solid (2.34 g, 69%): ¹H NMR (300 MHz, CDCl₃) δ 7.62-7.53 (m,2H), 7.00-6.93 (m, 1H), 3.64 (s, 2H), 3.43 (s, 1H), 2.59-2.36 (m, 4H),2.17-2.00 (m, 4H), 1.84-1.61 (m, 13H).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-3-cyclobutylbenzonitrile

To a cooled (0° C.) stirred solution of4-(adamantan-1-ylmethoxy)-3-(1-hydroxycyclobutyl)-benzonitrile (1.00 g,2.96 mmol) in methylene chloride (30 mL) was added triethylsilane (2.4mL, 14.80 mmol) followed by trifluoroacetic acid (2.3 mL, 29.60 mmol).The reaction mixture was stirred at 0° C. for 1.5 h and diluted with 1Maqueous sodium hydroxide solution (30 mL). The mixture was extractedwith methylene chloride (3×50 mL). The combined organic layers werewashed with brine (50 mL), dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography eluting with a 5% to 10% gradient of ethyl acetate inhexanes to afford 4-(adamantan-1-ylmethoxy)-3-cyclobutylbenzonitrile ascolorless solid in quantitative yield (0.95 g): MS (ES+) m/z 322.2(M+1);

Step 3. Preparation of 4-(adamantan-1-ylmethoxy)-3-cyclobutylbenzamide

Following the procedure as described in Example 38 step 3 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzonitrile with4-(adamantan-1-ylmethoxy)-3-cyclobutylbenzonitrile, the title compoundwas obtained as a colorless solid (0.88 g, 88%): MS (ES+) m/z 340.3(M+1);

Step 4. Preparation of4-(adamantan-1-ylmethoxy)-3-cyclobutyl-N-(methylsulfonyl)-benzamide

Following the procedure as described in Example 38 step 4 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with4-(adamantan-1-ylmethoxy)-3-cyclobutylbenzamide, the title compound wasobtained as a colorless solid (0.05 g, 12%): ¹H NMR (300 MHz, CDCl₃) δ8.48 (s, 1H), 7.70-7.61 (m, 2H), 6.87-6.80 (m, 1H), 3.80-3.65 (m, 1H),3.54 (s, 2H), 3.44 (s, 3H), 2.45-2.32 (m, 2H), 2.24-2.00 (m, 6H),1.94-1.61 (m, 13H); MS (ES+) m/z 418.2 (M+1);

Example 132 Synthesis of4-(adamantan-2-ylmethoxy)-3-cyclopropyl-N-(methylsulfonyl)benzamide

Step 1. Preparation of 4-(adamantan-2-ylmethoxy)-3-bromobenzonitrile

Following the procedure as described in Example 38 step 1 and makingvariation as required to replace adamantan-1-ylmethanol withadamantan-2-ylmethanol (J. Am. Chem. Soc. 2012, 134(2), 675), the titlecompound was obtained as a colorless solid (1.32 g, 44%): ¹H NMR (300MHz, CDCl₃) δ 7.84-7.79 (m, 1H), 7.62-7.54 (m, 1H), 6.99-6.92 (m, 1H),4.19-4.12 (m, 2H), 2.36-2.27 (m, 1H), 2.06-1.74 (m, 12H), 1.68-1.58 (m,2H);

Step 2. Preparation of4-(adamantan-2-ylmethoxy)-3-cyclopropylbenzonitrile

Following the procedure as described in Example 39 step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile with4-(adamantan-2-ylmethoxy)-3-bromobenzonitrile the title compound wasobtained as a colorless solid (0.68 g, 84%): MS (ES+) m/z 308.3 (M+1).

Step 3. Preparation of 4-(adamantan-2-ylmethoxy)-3-cyclopropylbenzamide

Following the procedure as described in Example 38 step 3 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzonitrile with4-(adamantan-2-ylmethoxy)-3-cyclopropylbenzonitrile, the title compoundwas obtained as a colorless solid (0.62 g, 95%): MS (ES+) m/z 326.3(M+1);

Step 4. Preparation of4-(adamantan-2-ylmethoxy)-3-cyclopropyl-N-(methylsulfonyl)-benzamide

Following the procedure as described in Example 38 step 3 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with4-(adamantan-2-ylmethoxy)-3-cyclopropylbenzamide, the title compound wasobtained as a colorless solid (0.09 g, 26%): ¹H NMR (300 MHz, CDCl₃) δ8.47 (s, 1H), 7.65-7.59 (m, 1H), 7.36-7.31 (m, 1H), 6.95-6.87 (m, 1H),4.19-4.10 (m, 2H), 3.43 (s, 3H), 2.35-2.25 (m, 1H), 2.21-2.08 (m, 1H),2.05-1.74 (m, 12H), 1.68-1.56 (m, 2H), 1.02-0.91 (m, 2H), 0.74-0.63 (m,2H); MS (ES+) m/z 404.3 (M+1);

Example 133 Synthesis of4-(adamantan-1-ylmethoxy)-2,5-dichloro-N-(methylsulfonyl)benzamide

Step 1. Preparation of 1-((4-bromo-2,5-dichlorophenoxy)methyl)adamantane

A mixture of 4-bromo-2,5-dichlorophenol (1.35 g, 5.58 mmol),adamantan-1-ylmethyl methanesulfonate (Fr. Demande, 2909090, May 30,2008) (1.5 g, 6.14 mmol), and potassium carbonate (0.85 g, 6.14 mmol) inN,N-dilmethylformamide (10 mL) was stirred at 65° C. for 16 h and at125° C. for 48 h. The reaction mixture was cooled down to ambienttemperature, diluted with water (40 mL) and extracted with ethyl acetate(2×50 mL). The combined organic layers were washed with brine (50 mL),dried over anhydrous magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography eluting with a5% to 10% gradient of ethyl acetate in hexanes to afford1-((4-bromo-2,5-dichlorophenoxy)methyl)adamantine as a colorless solid(1.7 g, 71%): MS (ES+) m/z 391.3 (M+1);

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-2,5-dichloro-N-(methylsulfonyl)-benzamide

Following the procedure as described in Example 47 step 5 and makingvariations as required to replace1-((4-bromo-2-chloro-5-fluorobenzyl)oxy)-adamantane with1-((4-bromo-2,5-dichlorophenoxy)methyl)adamantane, the title compoundwas obtained as a colorless solid (0.09 g, 10%): ¹H NMR (300 MHz, CDCl₃)δ 8.96 (s, 1H), 7.99 (s, 1H), 6.91 (s, 1H), 3.60 (s, 2H), 3.42 (s, 3H),2.09-2.01 (m, 3H), 1.83-1.64 (m, 12H); MS (ES−) m/z 430.2 (M−1), 432.2(M−1).

Example 134 Synthesis of4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N-((1-methyl-1H-imidazol-4-yl)sulfonyl)benzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid andmethanesulfonamide with 1-methyl-1H-imidazole-4-sulfonamide, the titlecompound was obtained as a colorless solid (0.16 g, 33%): ¹H NMR (300MHz, DMSO-d₆) δ 8.03-8.01 (m, 1H), 7.85-7.80 (m, 1H), 7.66-7.60 (m, 1H),7.21-7.14 (m, 1H), 3.73 (s, 3H), 3.70 (s, 2H), 1.98 (s, 3H), 1.78-1.57(m, 12H); MS (ES+) m/z 482.2 (M+1), 484.2 (M+1).

Example 135 Synthesis of5-chloro-4-((4,4-difluoroadamantan-1-yl)methoxy)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 4,4-difluoro-1-(hydroxymethyl)adamantane,the title compound was obtained as a colorless solid (0.21 g, 44%): ¹HNMR (300 MHz, CDCl₃) δ 8.64 (br s, 1H), 8.16-8.03 (m, 1H), 6.73-6.60 (m,1H), 3.63 (s, 2H), 3.03 (s, 6H), 2.37-2.25 (m, 2H), 2.11-1.84 (m, 5H),1.81-1.66 (m, 6H); MS (ES−) m/z 479.2 (M−1), 481.1 (M−1).

Example 136 Synthesis of4-(bicyclo[2.2.1]heptan-2-ylmethoxy)-5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 2-Norbornanemethanol, the title compound wasobtained as a colorless solid (0.17 g, 39%): ¹H NMR (300 MHz, CDCl₃) δ8.72-8.54 (m, 1H), 8.12-8.01 (m, 1H), 6.77-6.61 (m, 1H), 4.15-3.67 (m,2H), 3.01 (s, 6H), 2.49-2.21 (m, 3H), 2.10-1.74 (m, 1H), 1.64-1.05 (m,6H), 0.83-0.71 (m, 1H); MS (ES−) m/z 403.2 (M−1), 405.2 (M−1).

Example 137 Synthesis of5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-((octahydro-1H-4,7-methanoinden-5-yl)oxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with 2-tricyclo[5.2.1.0 {2,6}]decan-8-ol, thetitle compound was obtained as a colorless solid (0.03 g, 7%): ¹H NMR(300 MHz, CDCl₃) δ 8.70-8.58 (m, 1H), 8.10-8.03 (m, 1H), 6.70-6.58 (m,1H), 4.27-4.09 (m, 1H), 3.03 (s, 6H), 2.28 (s, 1H), 2.17-2.10 (m, 1H),2.02-1.65 (m, 6H), 1.65-1.56 (m, 1H), 1.54-1.39 (m, 2H), 1.36-1.17 (m,1H), 1.13-0.90 (m, 2H); MS (ES+) m/z 431.1 (M+1), 433.1 (M+1);

Example 138 Synthesis of4-(adamantan-2-ylmethoxy)-5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with adamantan-2-ylmethanol (J. Am. Chem. Soc.2012, 134(2), 675), the title compound was obtained as a colorless solid(0.14 g, 27%): ¹H NMR (300 MHz, CDCl₃) δ 8.75-8.57 (m, 1H), 8.13-8.03(m, 1H), 6.82-6.67 (m, 1H), 4.23-4.03 (m, 2H), 3.03 (s, 6H), 2.37-2.27(m, 1H), 2.04-1.73 (m, 11H), 1.69-1.54 (m, 3H); MS (ES−) m/z 443.2(M−1), 445.2 (M−1);

Example 139 Synthesis of5-chloro-N—(N,N-dimethylsulfamoyl)-2-fluoro-4-(((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)oxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide andadamantan-1-ylmethanol with [(1S)-endo]-(−)-borneol, the title compoundwas obtained as a colorless solid (0.17 g, 34%): ¹H NMR (300 MHz, CDCl₃)δ 8.64 (s, 1H), 8.20-8.00 (m, 1H), 6.67-6.43 (m, 1H), 4.47-4.25 (m, 1H),3.03 (s, 6H), 2.55-2.20 (m, 2H), 1.92-1.69 (m, 2H), 1.51-1.19 (m, 2H),1.19-0.74 (m, 10H); MS (ES−) m/z 431.2 (M−1), 433.2 (M−1).

Example 140 Synthesis of5-chloro-4-((3,3-dimethylcyclohexyl)oxy)-2-fluoro-N-(methylsulfonyl)-benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with3,3-dimethylcyclohexanol (Can. J. Chem. 1980, 58(18), 1993), the titlecompound was obtained as a colorless solid (0.14 g, 26%): ¹H NMR (300MHz, CDCl₃) δ 8.68 (s, 1H), 8.17-8.00 (m, 1H), 6.78-6.55 (m, 1H),4.55-4.33 (m, 1H), 3.42 (s, 3H), 2.12-2.02 (m, 1H), 1.86-1.73 (m, 2H),1.65-1.35 (m, 4H), 1.32-1.19 (m, 1H), 1.06-0.94 (m, 6H); MS (ES−) m/z376.1 (M−1), 378.1 (M−1).

Example 141 Synthesis of5-chloro-4-((4,4-dimethylcyclohexyl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with4,4-dimethylcyclohexanol (J. Am. Chem. Soc. 2009, 131(1), 251), thetitle compound was obtained as a colorless solid (0.24 g, 45%): ¹H NMR(300 MHz, CDCl₃) δ 1H NMR (300 MHz, CDCl₃) δ 8.68 (s, 1H), 8.17-8.03 (m,1H), 6.78-6.61 (m, 1H), 4.45-4.30 (m, 1H), 3.42 (s, 3H), 1.97-1.70 (m,4H), 1.63-1.48 (m, 2H), 1.38-1.17 (m, 2H), 1.01-0.95 (m, 6H); MS (ES−)m/z 376.1 (M−1), 378.1 (M−1).

Example 142 Synthesis of4-(adamantan-2-ylmethoxy)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol withadamantan-2-ylmethanol (J. Am. Chem. Soc. 2012, 134(2), 675), the titlecompound was obtained as a colorless solid (0.22 g, 36%): ¹H NMR (300MHz, CDCl₃) δ 8.69 (s, 1H), 8.22-7.99 (m, 1H), 6.88-6.62 (m, 1H),4.23-4.09 (m, 2H), 3.43 (s, 3H), 2.38-2.26 (m, 1H), 2.07-1.71 (m, 11H),1.69-1.51 (m, 3H); MS (ES+) m/z 416.1 (M+1), 418.1 (M+1);

Example 143 Synthesis of4-(bicyclo[2.2.1]heptan-2-ylmethoxy)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with 2-Norbornanemethanol,the title compound was obtained as a colorless solid (0.32 g, 46%): ¹HNMR (300 MHz, CDCl₃) δ 8.68 (s, 1H), 8.15-8.05 (m, 1H), 6.82-6.61 (m,1H), 4.16-3.70 (m, 2H), 3.43 (s, 3H), 2.58-2.15 (m, 3H), 2.12-1.74 (m,1H), 1.69-1.05 (m, 6H), 0.95-0.62 (m, 1H) MS (ES−) m/z 374.1 (M−1),376.1 (M−1);

Example 144 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-((octahydro-1H-4,7-methanoinden-5-yl)oxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with tricyclo[5.2.1.0{2,6}]decan-8-ol, the title compound was obtained as a colorless solid(0.21 g, 28%): ¹H NMR (300 MHz, CDCl₃) δ 8.76-8.57 (m, 1H), 8.18-7.95(m, 1H), 6.78-6.51 (m, 1H), 4.29-4.10 (m, 1H), 3.42 (s, 3H), 2.28 (br s,1H), 2.19-2.09 (m, 1H), 2.02-1.65 (m, 6H), 1.65-1.38 (m, 3H), 1.36-1.16(m, 1H), 1.13-0.87 (m, 2H); MS (ES−) m/z 400.1 (M−1), 402.1 (M−1).

Example 145 Synthesis of4-(bicyclo[2.2.1]heptan-2-yloxy)-5-chloro-2-fluoro-N-(methylsulfonyl)-benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with exo-Norborneol, thetitle compound was obtained as a colorless solid (0.33 g, 49%): ¹H NMR(300 MHz, CDCl₃) δ 8.68 (s, 1H), 8.14-8.04 (m, 1H), 6.73-6.59 (m, 1H),4.32-4.17 (m, 1H), 3.42 (s, 3H), 2.56-2.49 (m, 1H), 2.44-2.34 (m, 1H),1.89-1.79 (m, 1H), 1.76-1.49 (m, 4H), 1.32-1.11 (m, 3H): MS (ES−) m/z360.1 (M−1), 362.1 (M−1);

Example 146 Synthesis of4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-chloro-2-fluoro-N-(methylsulfonyl)-benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with(+)-endo-2-Norborneol, the title compound was obtained as a colorlesssolid (0.35 g, 52%): ¹H NMR (300 MHz, CDCl₃) δ 8.68 (s, 1H), 8.15-8.06(m, 1H), 6.69-6.57 (m, 1H), 4.76-4.61 (m, 1H), 3.42 (s, 3H), 2.72-2.63(m, 1H), 2.40-2.29 (m, 1H), 2.20-1.93 (m, 2H), 1.75-1.30 (m, 5H),1.23-1.11 (m, 1H); MS (ES−) m/z 360.1 (M−1), 362.1 (M−1);

Example 147 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((1R,2R,4S)-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl)oxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with (1R)-endo-(+)-Fenchylalcohol, the title compound was obtained as a colorless solid (0.28 g,37%): ¹H NMR (300 MHz, CDCl₃) δ 8.66 (s, 1H), 8.15-8.04 (m, 1H),6.75-6.63 (m, 1H), 4.02-3.92 (m, 1H), 3.42 (s, 3H), 2.18-2.03 (m, 1H),1.85-1.71 (m, 1H), 1.68-1.45 (m, 3H), 1.34-1.03 (m, 8H), 0.83 (s, 3H);MS (ES+) m/z 404.1 (M+1), 406.1 (M+1);

Example 148 Synthesis of5-chloro-2-fluoro-4-(((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with D-Menthol, the titlecompound was obtained as a colorless solid (0.24 g, 32%): ¹H NMR (300MHz, CDCl₃) δ 8.68 (s, 1H), 8.25-7.97 (m, 1H), 6.81-6.60 (m, 1H),4.23-3.98 (m, 1H), 3.42 (s, 3H), 2.20-2.03 (m, 2H), 1.83-1.44 (m, 5H),1.27-1.02 (m, 2H), 1.01-0.84 (m, 6H), 0.79-0.69 (m, 3H); MS (ES+) m/z406.1 (M+1), 408.1 (M+1);

Example 149 Synthesis of 5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((2s,3aR,4S,7R,7aS)-octahydro-1H-4,7-methanoinden-2-yl)methoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with ((2s,3aR,4S,7R,7aS)-octahydro-1H-4,7-methanoinden-2-yl)methanol, the titlecompound was obtained as a colorless solid (0.15 g, 35%). ¹H NMR (300MHz, DMSO-d₆) δ 12.10 (s, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.24 (d, J=12.5Hz, 1H), 3.92 (d, J=6.8 Hz, 2H), 3.34 (s, 3H), 2.49-2.36 (m, 2H),2.22-2.10 (m, 3H), 1.75-1.30 (m, 9H), 1.04-1.00 (m, 1H); MS (ES−) m/z414.1, 416.1 (M−1).

Example 150 Synthesis of6-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-(methylsulfonyl)nicotinamide

Step 1. Preparation of 6-(adamantan-1-ylmethoxy)-5-chloronicotinic acid

A mixture of 1-adamantylmethanol (5.32 g, 32.00 mmol),5,6-dichloronicotinic acid (6.14 g, 32.00 mmol) and potassiumtert-butoxide (8.3 g, 73.60 mmol) in anhydrous dimethyl sulfoxide (100mL) was heated to 80° C. under nitrogen for 1 h. The reaction mixturewas cooled to ambient temperature and diluted with ethyl acetate (500mL) and 1.0 M aqueous hydrochloric acid (300 mL). The layers wereseparated and the organic layer was washed with 1.0 M aqueoushydrochloric acid (100 mL), brine (2×100 mL); dried over anhydroussodium sulfate; filtered and concentrated in vacuo. The residue wastriturated with diethyl ether to afford the title compound as a whitesolid (4.32 g, 42%); ¹H NMR (300 MHz, DMSO-d₆) δ 13.23 (br s, 1H), 8.56(d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 3.95 (s, 1H), 2.00-1.88 (m,3H), 1.71-1.50 (m, 12H); MS (ES−) m/z: 320.3, 322.3 (M−1).

Step 2. Preparation of methyl6-(adamantan-1-ylmethoxy)-5-chloronicotinate

A solution of 6-(adamantan-1-ylmethoxy)-5-chloronicotinic acid (4.20 g,13.10 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (5.00 g,26.10 mmol), triethylamine (3.6 mL, 26.10 mmol) and methanol (1.05 mL,26.10 mmol) in methylene chloride (100 mL) was stirred under nitrogenfor 18 h. The reaction mixture was concentrated in vacuo and the residuewas dissolved in ethyl acetate (300 mL). The mixture was washed with a1:1(v/v) mixture of 1 M aqueous hydrochloric acid/brine (2×100 mL),brine (2×100 mL); dried over anhydrous sodium sulfate; filtered andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with 10% ethyl acetate in hexanes to afford the title compoundas a white solid (1.90 g, 43%); ¹H NMR (300 MHz, CDCl₃) δ 8.66-8.62 (m,1H), 8.19-8.16 (m, 1H), 3.99 (s, 2H), 3.89 (s, 3H), 2.04-1.96 (m, 3H),1.78-1.62 (m, 12H).

Step 3. Preparation of methyl6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinate

A mixture of methyl 6-(adamantan-1-ylmethoxy)-5-chloronicotinate (1.29g, 3.84 mmol), cyclopropylboronic acid (0.43 g, 4.99 mmol), potassiumphosphate (3.26 g, 15.40 mmol), tricyclohexylphosphine tetrafluoroborate(0.14 g, 0.38 mmol) and palladium acetate (0.04 g, 0.19 mmol) indegassed toluene (50 mL) and degassed water (5 mL) was refluxed undernitrogen for 7 h. The reaction mixture was cooled to ambient temperatureand diluted with ethyl acetate (100 mL), washed with water (50 mL),saturated ammonium chloride (50 mL) and brine (50 mL); dried overanhydrous sodium sulfate, filtered through diatomaceous earth andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with 5% ethyl acetate in hexanes to afford the title compound asa white solid (1.17 g, 89%); ¹H NMR (300 MHz, CDCl₃) δ 8.57 (d, J=2.2Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 3.95 (s, 2H), 3.85 (s, 3H), 2.09-1.96(m, 4H), 1.78-1.63 (m, 12H), 0.99-0.91 (m, 2H), 0.72-0.65 (m, 2H); MS(ES+) m/z: 342.22 (M+1).

Step 4. Preparation of 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinicacid

A mixture of methyl 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinate(1.17 g, 3.43 mmol) and lithium hydroxide monohydrate (0.58 g, 13.70mmol) in tetrahydrofuran (60 mL) and water (10 mL) was refluxed for 2 h.The reaction mixture was cooled to ambient temperature and diluted withethyl acetate (100 mL); washed with 1 M aqueous hydrochloric acid (80mL) and brine (80 mL); dried over anhydrous sodium sulfate; filtered andconcentrated in vacuo to afford the title compound which was usedwithout further characterization. MS (ES+) m/z: 328.2 (M+H).

Step 5. Preparation of6-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-(methylsulfonyl)-nicotinamide

A solution of 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid(0.43 g, 1.31 mmol) and carbonyldiimidazole (0.42 g, 2.62 mmol) inanhydrous tetrahydrofuran (22 mL) was refluxed under nitrogen for 30min. The reaction mixture was cooled to ambient temperature and treatedwith 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.59 mL, 3.93 mmol) andmethylsulfonamide (0.54 g, 3.93 mmol). The resulting mixture was stirredat ambient temperature for 2 h. The reaction mixture was diluted withethyl acetate (60 mL), washed with 1 M aqueous hydrochloric acid (2×30mL) and brine (50 mL); dried over anhydrous sodium sulfate; filtered andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with 30% ethyl acetate (containing 0.2% acetic acid) in hexanesto afford the title compound as a white solid (0.31 g, 58%); ¹H NMR (300MHz, DMSO-d₆) δ 12.01 (br s, 1H), 8.47 (d, J=2.5 Hz, 1H), 7.72 (d, J=2.5Hz, 1H), 3.93 (s, 2H), 3.33 (s, 3H), 2.07-1.98 (m, 1H), 1.97-1.90 (m,3H), 1.72-1.56 (m, 12H), 0.98-0.90 (m, 2H), 0.76-0.70 (m, 2H); MS (ES+)m/z: 405.2 (M+H).

Example 151 Synthesis of5-chloro-2-fluoro-N-methanesulfonyl-4-{[(1R,3S,5S)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-yl]methoxy}benzamideStep 1. Preparation of tert-butyl3-methylidene-8-azabicyclo[3.2.1]octane-8-carboxylate

To a solution of methyltriphenylphosphonium bromide (2.38 g, 6.6 mmol)in dry THF at 0° C. was added n-BuLi (2.7 mL, 2.5 M) dropwise. Afterstirring at 0° C. for 30 min, (1R,5S)-tert-butyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.2 mmol) wasadded and the mixture was stirred at 0° C. for additional 16 hrs. Thereaction was quenched by sat. NH₄Cl and extracted with EtOAc (50 mL×3)and purified by SGC (eluting with petroleum ether/ethyl acetate=20/1) togive target compound (130 mg, 27%). ¹H NMR (500 MHz, CDCl₃) δ4.77 (t,J=4.0 Hz, 2H), 4.21 (br s, 1H), 4.11 (br s, 1H), 2.43-2.33 (m, 2H), 2.01(s, 1H), 1.98 (s, 1H), 1.79 (d, J=3.0 Hz, 2H), 1.53-1.49 (m, 2H), 1.43(s, 9H).

Step 2. Preparation of tert-butyl3-(hydroxymethyl)-8-azabicyclo[3.2.1]-octane-8-carboxylate

To a solution of tert-butyl3-methylidene-8-azabicyclo[3.2.1]octane-8-carboxylate (0.8 g, 3.6 mmol)in dry THF (30 mL) at 0° C. was added a solution of borane-THF complex(4.7 mL, 1 M) and the resulting reaction was allowed to stir at roomtemperature for 48 hrs. The reaction was cooled to 0° C. then treatedwith NaOH (5.4 mL, 2 M) and hydrogen peroxide solution (1.8 mL, 35%).After stirring at room temperature for 3 hrs, the resulting mixture wasextracted with ethyl acetate (50 mL×3). The combined organic layers werewashed with brine (50 mL×3), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by SGC (eluting withpetroleum ether/ethyl acetate=20/1) to give the desired product (0.9 g,90%). LCMS (ESI) m/z: 239.9 [M−H]⁻.

Step 3. Preparation of 8-azabicyclo[3.2.1]octan-3-ylmethanol

A mixture of (1R,5S)-tert-butyl3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.9 g, 3.7mmol) and HCl in dioxane (2 N, 5.0 mL) was stirred at room temperaturefor 2 h. The mixture was concentrated in vacuo to afford the desiredproduct (300 mg crude), which was used in the next step without furtherpurification. LCMS (ESI) m/z: 139.7 [M−H]⁻.

Step 4. Preparation of8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-yl)methanol

A mixture of 8-aza-bicyclo[3.2.1]octan-3-ylmethanol (300 mg, 2.4 mmol),2,2,2-trifluoroethyl trifluoromethanesulfonate (660 mg, 2.8 mmol) andNaHCO₃ (400 mg, 4.8 mmol) in ethanol (10 mL) was stirred at 80° C. for 4hrs. The mixture was diluted with ethyl acetate (100 mL), washed withbrine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by SGC (eluting with petroleum ether/ethyl acetate=10/1) togive the desired product (180 mg, 38% yield). LCMS (ESI) m/z: 222.0[M−H]⁻.

Step 5. Preparation of5-chloro-2-fluoro-N-methanesulfonyl-4-{[(1R,3S,5S)-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-yl]methoxy}benzamide

A mixture of(8-(2,2,2-trifluoroethyl)-8-aza-bicyclo[3.2.1]octan-3-yl)methanol (60mg, 0.27 mmol), 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (78mg, 0.27 mmol) and potassium t-butoxide (60 mg, 0.54 mmol) in DMSO (2mL) was stirred at room temperature for 16 hrs. The reaction wasquenched with water, extracted with EtOAc. The combined organic layerswere concentrated in vacuo and the residue was purified by reverse phaseCombiflash (20%-50% MeCN in 0.1% NH₄HCO₃) to give the desired product(22.5 mg, 23%). LCMS (ESI) Method A: RT=5.12 min, m/z: 472.7[M+H]⁺;¹H-NMR (500 MHz, MeOD-d₄) δ 7.81 (d, J=7.5 Hz, 1H), 7.01 (d, J=12.0 Hz,1H), 4.09 (d, J=8.0 Hz, 2H), 3.33-3.29 (m, 5H), 3.06-3.00 (m, 2H),2.31-2.18 (m, 3H), 2.04-2.01 (m, 2H), 1.70-1.62 (m, 4H).

Example 152 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-((5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)benzamide

Step 1. Preparation of 5-chloro-2-fluoro-4-methylbenzoic acid

To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (11.3 g, 50mmol) in dry THF (100 mL) was added isopropylmagnesium chloride (30 mL,2 M) dropwise. After stirring at room temperature for 30 min, dry CO₂was added and the mixture was stirred at room temperature for additional30 min. The reaction was quenched by sat. NH₄Cl and extracted with EtOAc(100 mL×3). The combined organic layers were washed with water (50mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated to givethe desired product (4.7 g, 49%). LCMS (ESI) m/z: 187.0 [M−H]⁻.

Step 2. Preparation of5-chloro-2-fluoro-4-methyl-N-(methylsulfonyl)benzamide

A solution of 5-chloro-2-fluoro-4-methylbenzoic acid (1 g, 5.2 mmol),methanesulfonamide (760 mg, 8.0 mmol),1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.5 g, 8.0mmol) and 4-dimethylaminopyridine (1.5 g, 8.0 mmol) in DCM (20 mL) wasstirred at room temperature for 16 hrs. The reaction was quenched bywater (5 mL), adjusted pH to 1 with HCl (1 M) and the resulting mixturewas extracted with DCM (100 mL×3). The combined organic layers wereconcentrated in vacuo and the residue was recrystallized with petroleumether and ethyl acetate to give desired product (1.6 g crude). LCMS(ESI) m/z: 263.9 [M+H]⁺.

Step 3. Preparation of4-(bromomethyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

A mixture of 5-chloro-2-fluoro-4-methyl-N-(methylsulfonyl)benzamide (0.8g, 3.0 mmol), N-bromosuccinimide (1.6 g, 9.0 mmol) andazodiisobutyronitrile (16 mg, 0.09 mmol) in 1,2-dichloroethane (20 mL)was stirred at 90° C. for 16 hrs. The reaction was quenched with Na₂SO₃(10 mL, 10%), extracted with 1,2-dichloroethane (20 mL×3), dried overanhydrous Na₂SO₄, concentrated and the residue was used in next stepwithout further purification (1.1 g, crude). LCMS (ESI) m/z: 342.0[M+H]⁺.

Step 4. Preparation of5-chloro-2-fluoro-N-(methylsulfonyl)-4-((5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)benzamide

A mixture of4-(bromomethyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide (40 mg,0.12 mmol), 5,6,7,8-tetrahydronaphthalen-2-ol (40 mg, 0.24 mmol) andK₂CO₃ (60 mg, 0.24 mmol) in acetone (10 mL) was stirred at 50° C. for 4h. The reaction was filtered and purified by reverse phase Combiflash(20%-50% MeCN in 0.1% formic acid) to give target compound (7.7 mg, 16%)as a white solid. LCMS (ESI) Method A: RT=4.12 min, m/z: 412.1 [M+H]⁺.¹H-NMR (400 MHz, MeOD-d₄) δ 7.80 (d, J=6.0 Hz, 1H), 7.37 (d, J=5.6 Hz,1H), 6.97 (d, J=8.4 Hz, 1H), 6.74-6.68 (m, 2H), 5.11 (s, 2H), 3.20 (s,3H), 2.74-2.70 (m, 4H), 1.80-1.77 (m, 4H).

Example 153 Synthesis of5-chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethyl-cyclopropyl)methoxy)benzamide

Step 1. Preparation of 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide

To a mixture of 5-chloro-2,4-dilfluorobenzoic acid (0.291 g, 1.51 mmol),1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.438 g, 2.29mmol), and 4-dimethylaminopyridine (0.420 g, 3.44 mmol) in THF (5 mL)was added methanesulfonamide (0.222 g, 2.33 mmol). After stirred at roomtemperature for 18 hrs, the mixture was diluted with DCM (10 mL) andwashed with 2 N HCl (15 mL×2). The organic layer was dried over Na₂SO₄and concentrated in vacuo to afford5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (0.388 g, 95%) as awhite solid. LCMS (ESI) m/z: 268.1 [M−H]⁺.

Step 2. Preparation of (2,2,3,3-Tetramethylcyclopropyl)methanol

To a stirred solution of 2,2,3,3-tetramethylcyclopetanecarboxylic acid(500 mg, 3.50 mmol) in THF (25 mL) at 0° C. was added boranedimethylsulfide complex in THF (2.0 M, 1.8 mL, 3.5 mmol). The mixturewas then warmed to 50° C. and stirred for 3 h. After cooling to roomtemperature, methanol (10 mL) was added carefully. The resulting mixturewas filtered and the filtrate was concentrated to afford(2,2,3,3-tetramethylcyclopropyl)methanol (250 mg, 56%) as an oil. ¹H NMR(500 MHz, CDCl₃): δ 3.67 (d, J=8.0 Hz, 2H), 1.10 (s, 6H), 1.02 (s, 6H),0.54 (t, J=8.0 Hz, 1H).

Step 3. Preparation of5-Chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethyl-cyclopropyl)methoxy)benzamide

To a stirred solution of (2,2,3,3-tetramethylcyclopropyl)methanol (48mg, 0.37 mmol) in dry DMSO (5 mL) was added potassium t-butoxide (124mg, 1.11 mmol) at room temperature. After stirring for 30 min,5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (50 mg, 0.20 mmol) wasadded and the reaction mixture was stirred at room temperature for 16hrs. The mixture was cooled to 0° C., quenched by hydrochloride acid(1N, 30 mL) and extracted with ethyl acetate (50 mL). The organic layerwas washed with water (40 mL×2), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude product was purified byprep HPLC (20%-50% MeCN in 0.1% formic acid) to afford the titlecompound as a white solid (7 mg, 10%). LCMS (ESI) Method A: RT=5.28 min,m/z: 268.1 [M-109]⁺; ¹H-NMR (500 MHz, DMSO-d₆): δ 8.13 (br s, 1H), 7.76(d, J=8.0 Hz, 1H), 7.21-7.10 (m, 1H), 4.18 (d, J=7.0 Hz, 2H), 3.02 (s,3H), 1.10 (s, 6H), 1.03 (s, 6H), 0.74 (t, J=7.5 Hz, 1H).

Example 154 Synthesis of5-Chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethyl-cyclopropyl)methoxy)benzamide

The synthetic procedure was the same as Example 152. LCMS (ESI) MethodB: RT=6.09 min, m/z: 455.1 [M+H]⁺; ¹H-NMR (500 MHz, MeOD-d₄): δ 7.76 (d,J=6.5 Hz, 1H), 7.43 (d, J=10.5 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H),6.78-6.76 (m, 1H), 6.72 (s, 1H), 5.10 (s, 2H), 2.67 (t, J=13 Hz, 2H),2.51-2.47 (m, 5H), 1.50 (t, J=13.5 Hz, 2H), 0.93 (s, 6H).

Example 155 Synthesis of5-chloro-4-((7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)-2-fluoro-N-(N-methylsulfamoyl)benzamide

The synthetic procedure was the same as Example 152. LCMS (ESI) MethodA: RT=6.34 min, m/z: 455.1 [M+H]⁺; ¹H-NMR (500 MHz, MeOD-d₄): δ 7.75 (d,J=6.5 Hz, 1H), 7.41 (d, J=10.5 Hz, 1H), 6.95 (d, J=7.5 Hz, 1H),6.78-6.76 (m, 2H), 5.10 (s, 2H), 2.72 (t, J=7.0 Hz, 2H), 2.46-2.42 (m,5H), 1.49 (t, J=6.5 Hz, 2H), 0.93 (s, 6H).

Example 156 Synthesis of5-chloro-4-((7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

Step 1. Preparation of tert-butyl5-chloro-4-((7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)-2-fluorobenzoate

A solution of tert-butyl 4-(bromomethyl)-5-chloro-2-fluorobenzoate (200mg, 0.62 mmol), 7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-ol (109 mg,0.62 mmol) and potassium carbonate (257 mg, 1.86 mmol) in acetone (20mL) was stirred at 50° C. for 4 hrs. The reaction mixture was filtered,the filtrate was concentrated and purified by SGC (eluting withpetroleum ether/ethyl acetate from 100/1 to 25/1) to get the desiredcompound (220 mg, 85%).

Step 2. Preparation of5-chloro-4-((7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)-2-fluorobenzoicacid

To a solution of tert-butyl5-chloro-4-((7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)-2-fluorobenzoate(220 mg, 0.53 mmol) in DCM (5 mL) was added trifluoroactic acid (5 mL).After stirred at room temperature for 3 h, the reaction mixture wasconcentrated under reduced pressure and the residue was used in nextstep without further purification (0.22 g, crude). LCMS (ESI) m/z: 361.0[M−H]⁺.

Step 3. Preparation of5-chloro-4-((7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

A solution of5-chloro-4-((7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)-2-fluorobenzoicacid (50 mg, 0.14 mmol), dimethyl(sulfamoyl)amine (326 mg, 0.20 mmol),1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg, 0.20mmol) and 4-dimethylaminopyridine (38 mg, 0.20 mmol) in DCM (3 mL) wasstirred at room temperature for 16 hrs. The reaction was quenched withwater (5 mL), adjusted pH to 5 with HCl (1M) and extracted with DCM (30mL×3). The combined organic layers were concentrated and purified byreverse phase combiflash (20%-50% MeCN in 0.1% formic acid) to give thedesired product (14.6 mg, 19%) as a white solid. LCMS (ESI) Method A:RT=6.47 min, m/z 466.9 [M−H]⁺; ¹H-NMR (500 MHz, MeOD-d₄) δ 7.63 (d,J=5.5 Hz, 1H), 7.32 (d, J=11.0 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H),6.66-6.63 (m, 1H), 6.56 (d, J=2.0 Hz, 1H), 5.03 (s, 2H), 2.83 (s, 6H),2.64 (t, J=13.0 Hz, 2H), 2.40 (s, 2H), 1.46 (t, J=13.5 Hz, 2H), 0.88 (s,6H).

Example 157 Synthesis of5-chloro-4-((6,6-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)-N—(N,N-dimethylsulfamoyl)-2-fluorobenzamide

The synthetic procedure was the same as Example 156. LCMS (ESI) MethodA: RT=6.61 min, m/z: 468.7 [M+H]⁺; ¹H-NMR (500 MHz, DMSO-d₆) δ 7.76 (d,J=6.0 Hz, 1H), 7.37 (d, J=11.0 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H),6.77-6.75 (m, 2H), 5.13 (s, 2H), 2.89 (s, 6H), 2.80 (t, J=6.5 Hz, 2H),2.48 (s, 2H), 1.57 (t, J=6.5 Hz, 2H), 0.99 (s, 6H).

Example 158 Synthesis of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

Step 1. Preparation of5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)benzoic acid

To a solution of (1-(trifluoromethyl)cyclohexyl)methanol (3.20 g, 17.57mmol) in anhydrous dimethylsulfoxide (50 ml) was added potassiumtert-butoxide (4.90 g, 43.66 mmol) and the reaction mixture was stirredat ambient temperature for 30 minutes. 5-chloro-2,4-difluorobenzoic acid(3.38 g, 17.55 mmol) was added to the reaction mixture, and stirring wascontinued for 2 hours. The reaction mixture was acidified to pH=1 with5% aqueous hydrochloric acid solution and extracted with ethyl acetate,the combined organic extracts was washed with brine; dried overanhydrous sodium sulfate and concentrated in vacuo. Purification of theresidue by column chromatography (30% ethyl acetate in hexanes) affordedthe title compound (5.20 g, 83%) containing o-substituted regioisomer,which was used for next step without further purification: MS (ES−) m/z355.2, 353.2 (M−1).

Step 2. Preparation of tert-butyl5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoate

To a solution of5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoicacid (5.20 g, 14.65 mmol) and N,N-dimethylpyridin-4-amine (0.5 g, 4.16mmol) in tert-butanol (50 mL) was added di-tert-butyldicarbonate (9.60g, 43.98 mmol). The reaction mixture was heated at 50° C. for 6 hours.Additional di-tert-butyldicarbonate (4.80 g, 21.99 mmol) was added;stirring was continued for 17 hours at 50° C. and concentrated in vacuo.The residue was purified by column chromatography (5% ethyl acetate inhexanes) to afford the title compound (4.37 g, 72%): ¹H NMR (300 MHz,CDCl₃) δ 7.86 (d, J=7.5 Hz, 1H), 6.63 (d, J=11.7 Hz, 1H), 4.10 (s, 2H),1.97-1.88 (m, 3H), 1.76-1.62 (m, 5H), 1.56 (s, 9H), 1.48-1.23 (m, 2H).

Step 3. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoate

To a mixture of tert-butyl5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoate(4.37 g, 10.63 mmol), cyclopropylboronic acid (1.37 g, 15.93 mmol),potassium phosphate (10.15 g, 47.81 mmol) and tricyclohexylphosphinetetrafluoroborate (0.39 g, 1.06 mmol) in toluene (60 mL) and water (3mL) under a nitrogen atmosphere was added palladium acetate (0.12 g,0.53 mmol). The reaction mixture was heated at 100° C. for 18 hours andthen cooled to ambient temperature. Water (20 mL) was added and themixture, and extracted with ethyl acetate, the combined organic extractswas washed with brine; dried over anhydrous sodium sulfate andconcentrated in vacuo. Purification of the residue by columnchromatography (5% ethyl acetate in hexanes) afforded the title compound(3.70 g, 83%): ¹H NMR (300 MHz, CDCl₃) δ 7.40 (d, J=8.4 Hz, 1H), 6.51(d, J=12.3 Hz, 1H), 4.07 (s, 2H), 1.99-1.88 (m, 4H), 1.76-1.62 (m, 5H),1.55 (s, 9H), 1.48-1.24 (m, 2H), 0.91-0.82 (m, 2H), 0.62-0.55 (m, 2H).

Step 4. Preparation of5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid

To a solution of tert-butyl5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)-methoxy)benzoate(3.70 g, 8.88 mmol) in dichloromethane (20 mL) was added trifluoroaceticacid (10 ml). The reaction mixture was stirred at ambient temperaturefor 2 hours and then concentrated in vacuo. The residue was trituratedin hexanes (10 mL), the solid was filtered and dried to give the titlecompound (2.20 g, 69%): ¹H NMR (300 MHz, CDCl₃) δ 7.54 (d, J=8.1 Hz,1H), 6.59 (d, J=12.3 Hz, 1H), 4.11 (s, 2H), 2.03-1.88 (m, 3H), 1.76-1.60(m, 5H), 1.50-1.21 (m, 3H), 0.94-0.83 (m, 2H), 0.64-0.55 (m, 2H); MS(ES+) m/z 361.1 (M+1).

Step 5. Preparation of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

To a stirred solution of5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid (0.36 g, 1.00 mmol) in dichloromethane (20 mL) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g,1.50 mmol) and 4-dimethylaminopyridine (0.28 g, 2.30 mmol). The reactionwas stirred at ambient temperature for 10 minutes, methanesulfonamide(0.15 g, 1.56 mmol) was added and the stirring was continued at ambienttemperature for 17 hours. 5% aqueous hydrochloric acid solution (10 mL)were added and diluted with ethyl acetate (100 mL), washed with waterand brine; dried over anhydrous sodium sulfate and concentrated invacuo. Purification of the residue by column chromatography (30% ethylacetate in hexanes) afforded the title compound (0.27 g, 62%) as acolorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.70 (br s, 1H), 7.59 (d,J=9.0 Hz, 1H), 6.59 (d, J=14.1 Hz, 1H), 4.12 (s, 2H), 3.39 (s, 3H),2.03-1.88 (m, 3H), 1.76-1.63 (m, 5H), 1.48-1.23 (m, 3H), 0.94-0.87 (m,2H), 0.64-0.58 (m, 2H); MS (ES−) m/z 436.2 (M−1).

Example 159 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace methanesulfonamide withazetidine-1-sulfonamide, the title compound was obtained (0.30 g, 63%)as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.63 (br s, 1H), 7.62(d, J=9.0 Hz, 1H), 6.59 (d, J=14.1 Hz, 1H), 4.23 (t, J=7.5 Hz, 4H), 4.12(s, 2H), 2.31-2.20 (m, 2H), 2.05-1.89 (m, 3H), 1.78-1.62 (m, 5H),1.48-1.23 (m, 3H), 0.93-0.87 (m, 2H), 0.66-0.59 (m, 2H); MS (ES−) m/z477.2 (M−1).

Example 160 Synthesis of5-cyclopropyl-2-fluoro-N-((3-fluoroazetidin-1-yl)-sulfonyl)-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 158 step 5 and makingvariations as required to replace methanesulfonamide with3-fluoroazetidine-1-sulfonamide, the title compound was obtained (0.27g, 54%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.70 (br s, 1H),7.60 (d, J=9.0 Hz, 1H), 6.60 (d, J=14.1 Hz, 1H), 5.39-5.13 (m, 1H),4.52-4.32 (m, 4H), 4.12 (s, 2H), 2.31-2.20 (m, 2H), 2.05-1.87 (m, 2H),1.78-1.62 (m, 4H), 1.48-1.23 (m, 3H), 0.94-0.87 (m, 2H), 0.65-0.59 (m,2H); MS (ES−) m/z 495.1 (M−1).

Example 161 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace methanesulfonamide withcyclopropanesulfonamide, the title compound was obtained (0.24 g, 51%)as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J=15.9 Hz, 1H),7.61 (d, J=9.3 Hz, 1H), 6.59 (d, J=14.1 Hz, 1H), 4.12 (s, 2H), 3.13-3.03(m, 1H), 2.04-1.88 (m, 3H), 1.76-1.63 (m, 5H), 1.48-1.23 (m, 5H),1.69-1.08 (m, 2H), 0.94-0.86 (m, 2H), 0.65-0.58 (m, 2H); MS (ES−) m/z462.2 (M−1); MS (ES+) m/z 464.1 (M+1).

Example 162 Synthesis of5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)-sulfonyl)-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace methanesulfonamide with2-methoxyethanesulfonamide, the title compound was obtained (0.03 g, 6%)as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.62 (d, J=15.6 Hz, 1H),7.59 (d, J=9.0 Hz, 1H), 6.59 (d, J=14.1 Hz, 1H), 4.12 (s, 2H), 3.87-3.75(m, 4H), 3.29 (s, 3H), 2.03-1.88 (m, 3H), 1.78-1.63 (m, 5H), 1.48-1.28(m, 3H), 0.94-0.86 (m, 2H), 0.65-0.58 (m, 2H); MS (ES−) m/z 480.1 (M−1);MS (ES+) m/z 482.0 (M+1).

Example 163 Synthesis of5-cyclopropyl-2-fluoro-N-(N-methylsulfamoyl)-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 158 step 5 and makingvariations as required to replace methanesulfonamide with(methylsulfamoyl)amine, the title compound was obtained (0.22 g, 65%) asa colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.69 (d, J=15.3 Hz, 1H),7.58 (d, J=9.0 Hz, 1H), 6.59 (d, J=14.1 Hz, 1H), 5.26-5.22 (m, 1H), 4.12(s, 2H), 2.75 (d, J=4.5 Hz, 3H), 2.04-1.88 (m, 3H), 1.74-1.63 (m, 5H),1.50-1.27 (m, 3H), 0.94-0.86 (m, 2H), 0.64-0.58 (m, 2H); MS (ES−) m/z451.1 (M−1). MS (ES+) m/z 453.0 (M+1).

Example 164 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzamide

Step 1. Preparation of5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzoicacid

To a solution of (1-(trifluoromethyl)cyclopentyl)methanol (2.80 g, 16.65mmol) in anhydrous dimethylsulfoxide (50 ml) was added potassiumtert-butoxide (4.50 g, 40.106 mmol) and the reaction mixture was stirredat ambient temperature for 30 minutes. 5-chloro-2,4-difluorobenzoic acid(3.20 g, 16.62 mmol) was added to the reaction mixture, and stirring wascontinued for 2 hours. The reaction mixture was acidified to pH=1 with5% aqueous hydrochloric acid solution and extracted with ethyl acetate,the combined organic extracts was washed with brine; dried overanhydrous sodium sulfate and concentrated in vacuo. Purification of theresidue by column chromatography (30% ethyl acetate in hexanes) affordedthe title compound (5.00 g, 88%) containing o-substituted regioisomer,which was used for next step without further purification: MS (ES−) m/z339.2, 341.2 (M−1).

Step 2. Preparation ofN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzamide

To a stirred solution of5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclopentyl)-methoxy)benzoicacid (0.34 g, 1.00 mmol) in dichloromethane (20 mL) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g,1.50 mmol) and 4-dimethylaminopyridine (0.28 g, 2.30 mmol). The reactionmixture was stirred at ambient temperature for 10 minutes,azetidine-1-sulfonamide (0.20 g, 1.50 mmol) was added and the stirringwas continued at ambient temperature for 17 hours. 5% aqueoushydrochloric acid solution (10 mL) were added and diluted with ethylacetate (100 mL), washed with water and brine; dried over anhydroussodium sulfate and concentrated in vacuo. Purification of the residue bycolumn chromatography (30% ethyl acetate in hexanes) afforded the titlecompound (0.22 g, 46%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.61 (br s, 1H), 8.11 (d, J=7.2 Hz, 1H), 6.69 (d, J=12.9 Hz, 1H), 4.22(br s, 4H), 4.03 (s, 2H), 2.31-2.17 (m, 2H), 2.08-1.92 (m, 2H),1.89-1.70 (m, 6H); MS (ES+) m/z 459.0, 461.0 (M+1); MS (ES−) m/z 457.1,459.1 (M−1).

Example 165 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzamide

To a mixture ofN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzamide(0.18 g, 0.39 mmol), cyclopropylboronic acid (0.40 g, 4.65 mmol) andpotassium phosphate (2.55 g, 12.00 mmol) in toluene (20 mL) and water(1.0 mL) was sparged with a nitrogen atmosphere for 10 minutes,tricyclohexylphosphine tetrafluoroborate (0.17 g, 0.48 mmol) andpalladium acetate (0.05 g, 0.22 mmol) was added to this reactionmixture. The reaction mixture was heated to 100° C. for 96 hours under anitrogen atmosphere and then cooled to ambient temperature. 5% aqueoushydrochloric acid (20 mL) was added and the mixture was extracted withethyl acetate (100 mL×3), the combined organics were washed with brine;dried over anhydrous sodium sulfate and concentrated in vacuo.Purification of the residue by column chromatography (10% to 30%gradient ethyl acetate in hexanes) afforded the title compound (0.11 g,61%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.63 (d, J=16.2 Hz,1H), 7.62 (d, J=9.0 Hz, 1H), 6.57 (d, J=14.1 Hz, 1H), 4.23 (t, J=7.5 Hz,4H), 3.99 (s, 2H), 2.31-2.20 (m, 2H), 2.08-1.94 (m, 3H), 1.89-1.70 (m,6H), 0.95-0.88 (m, 2H), 0.67-0.60 (m, 2H); MS (ES+) m/z 465.1 (M+1), MS(ES−) m/z 463.1 (M−1).

Example 166 Synthesis of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((trans-4-(trifluoromethyl)-cyclohexyl)oxy)benzamide

Following the procedure as described in Example 165 and makingvariations as required to replaceN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzamidewith5-chloro-2-fluoro-N-(methylsulfonyl)-4-((trans-4-(trifluoromethyl)cyclohexyl)oxy)benzamide,the title compound was obtained (0.24 g, 57%) as a colorless solid: ¹HNMR (300 MHz, CDCl₃) δ 8.68 (d, J=16.2 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H),6.55 (d, J=14.7 Hz, 1H), 4.69-4.65 (m, 1H), 3.39 (s, 3H), 2.24-1.95 (m,4H), 1.83-1.55 (m, 6H), 0.97-0.89 (m, 2H), 0.66-0.60 (m, 2H); MS (ES−)m/z 422.2 (M−1); MS (ES+) m/z 424.1 (M+1).

Example 167 Synthesis of5-chloro-4-(((4,4-difluoro-1-methylcyclohexyl)oxy)methyl)-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of1-bromo-5-chloro-4-(((4,4-difluoro-1-methylcyclohexyl)oxy)-methyl)-2-fluorobenzene

To a solution of 4-bromo-2-chloro-5-fluorobenzyl2,2,2-trichloroacetimidate (4.00 g, 10.40 mmol) and4,4-difluoro-1-methylcyclohexanol (1.21 g, 8.05 mmol) in methylenechloride (50 mL) and cyclohexane (25 mL) was addedtrifluoromethanesulfonic acid (0.1 mL, 0.14 mmol) at 0 ?C. The reactionmixture was stirred for 56 hours at ambient temperature and quenched byaddition of saturated sodium bicarbonate solution (10 mL), and thendiluted with methylene chloride (100 mL). The organic layer wasseparated and washed with brine; dried over anhydrous sodium sulfate andconcentrated in vacuo. Purification of the residue by columnchromatography (5% ethyl acetate in hexanes) and recrystallization frommethanol afforded the title compound (0.54 g, 17%) as a colorless solid:¹H NMR (300 MHz, CDCl₃) δ 7.51 (d, J=6.0 Hz, 1H), 7.30 (d, J=9.3 Hz,1H), 4.37 (s, 2H), 2.11-1.86 (m, 6H), 1.72-1.59 (m, 2H), 1.26 (s, 3H).

Step 2. Preparation of5-chloro-4-(((4,4-difluoro-1-methylcyclohexyl)-oxy)methyl)-2-fluoro-N-(methylsulfonyl)benzamide

A mixture of1-bromo-5-chloro-4-(((4,4-difluoro-1-methylcyclohexyl)-oxy)methyl)-2-fluorobenzene(0.20 g, 0.50 mmol), methanesulfonamide (0.14 g, 1.50 mmol),molybdenumhexacarbonyl (0.13 g, 0.50 mmol) and triethylamine (0.3 mL,2.15 mmol) in dioxane was sparged with nitrogen for 5 minutes, xantphos(0.05 g, 0.09 mmol) and palladium acetate (0.01 g, 0.045 mmol) wereadded to the reaction mixture. The reaction mixture was heated at 100 ECfor 1 hour under microwave irradiation (300 psi) and then cooled toambient temperature, diluted with methylene chloride (100 mL) andsaturated ammonium chloride (20 mL). The organic layer was washed withbrine; dried over anhydrous sodium sulfate and concentrated in vacuo.Purification of the residue by column chromatography (10% to 30%gradient ethyl acetate in hexanes) afforded the title compound (0.06 g,28%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.78 (d, J=15.0 Hz,1H), 8.05 (d, J=6.9 Hz, 1H), 7.42 (d, J=12.9 Hz, 1H), 4.47 (s, 2H), 3.42(s, 3H), 2.11-1.89 (m, 6H), 1.74-1.62 (m, 2H), 1.27 (s, 3H); MS (ES−)m/z 412.1, 414.1 (M−1).

Example 168 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(spiro[3.5]nonan-7-ylmethoxy)benzamide

To a solution of spiro[3.5]nonan-7-ylmethanol (0.58 g, 3.76 mmol) inanhydrous dimethyl sulfoxide (20 mL) was added potassium t-butoxide(1.05 g, 9.35 mmol) at ambient temperature. After stirring at ambienttemperature for 30 minutes,N-(azetidin-1-ylsulfonyl)-5-chloro-2,4-difluorobenzamide (1.17 g, 3.76mmol) was added to the reaction mixture; stirring was continued atambient temperature for 2 hours. The mixture was cooled to 0° C. andquenched with 5% aqueous hydrochloride acid (10 mL) followed byextraction with ethyl acetate (100 mL). The organic layer was washedwith water (2×40 mL) and brine, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated in vacuo, the crude product waspurified by silica gel column chromatography using 10-40% ethyl acetate(containing 0.2% acetic acid) in hexanes to afford the title compound asa colorless solid (0.60 g, 36%): ¹H NMR (300 MHz, CDCl₃) δ 8.60 (d,J=15.6 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 6.66 (d, J=13.8 Hz, 1H), 4.23(t, J=7.8 Hz, 4H), 3.82 (d, J=6.3 Hz, 2H), 2.32-2.20 (m, 2H), 1.88-1.66(m, 11H), 1.35-1.24 (m, 2H), 1.18-1.05 (m, 2H); MS (ES+) m/z 445.1,447.1 (M+1), MS (ES−) m/z 443.2, 445.2 (M−1).

Example 169 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-(spiro[3.5]nonan-7-ylmethoxy)benzamide

Following the procedure as described in Example 165 and makingvariations as required to replaceN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzamidewithN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(spiro[3.5]nonan-7-ylmethoxy)benzamide,the title compound was obtained (0.06 g 19%) as a colorless solid: ¹HNMR (300 MHz, CDCl₃) δ 8.66 (d, J=16.2 Hz, 1H), 7.59 (d, J=9.1 Hz, 1H),6.56 (d, J=14.5 Hz, 1H), 4.24 (t, J=7.7 Hz, 4H), 3.81 (d, J=6.1 Hz, 2H),2.26 (q, J=7.7 Hz, 2H), 2.09-2.00 (m, 1H), 1.90-1.63 (m, 10H), 1.36-1.10(m, 5H), 0.96-0.89 (m, 2H), 0.69-0.63 (m, 2H); MS (ES−) m/z 449.3 (M−1).

Example 170 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-(2-(4,4-difluorocyclohexyl)-ethoxy)-2-fluorobenzamide

Step 1. Preparation of tert-butyl5-chloro-4-(2-(4,4-difluorocyclohexyl)-ethoxy)-2-fluorobenzoate

To a of solution ethyl 2-(4,4-difluorocyclohexyl)acetate (1.44 g, 7.00mmol) in anhydrous tetrahydrofuran (23 mL) and anhydrous methanol (0.6mL) was added lithium borohydride (4 M in tetrahydrofuran, 3.5 mL, 16.00mmol) at 0° C. and the mixture was heated to reflux for 2 hours. Themixture was then cooled to 0° C. and quenched with methanol until gasevolution ceased. The solution was warmed to ambient temperature thenpoured into water (50 mL). The aqueous layer was separated and extractedwith diethyl ether (3×20 mL). The combined organic layers were washedwith brine; dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the crude alcohol (0.98 g), which wasdissolved in anhydrous dimethylsulfoxide (6 mL), tert-butyl5-chloro-2,4-difluorobenzoate (1.64 g, 6.60 mmol) and cesium carbonate(4.11 g, 12.6 mmol) was added. The reaction mixture was heated at 70° C.for 2 hours and then cooled to ambient temperature and diluted withwater (60 mL) and extracted with ethyl acetate (4×20 mL). The combinedorganic layers were washed with brine; dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (0% to 10% ethyl acetate in hexanes) to afford thetitle compound (0.681 g, 29%): ¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J=7.7Hz, 1H), 6.63 (d, J=12.1 Hz, 1H), 4.08 (t, J=6.6 Hz, 2H), 2.17-2.07 (m,2H), 1.77-1.62 (m, 5H), 1.57 (s, 9H), 1.42-1.29 (m, 4H).

Step 2. Preparation of tert-butyl5-cyclopropyl-4-(2-(4,4-difluorocyclohexyl)ethoxy)-2-fluorobenzoate

To a solution of tert-butyl5-chloro-4-(2-(4,4-difluorocyclohexyl)ethoxy)-2-fluorobenzoate (0.681 g,1.70 mmol) in toluene-water (v/v 20:1, 10.5 mL) was addedcyclopropylboronic acid (0.227 g, 2.60 mmol), tricyclohexylphosphinetetrafluoroborate (0.064 g, 0.17 mmol) and potassium phosphate tribasic(1.658 g, 7.80 mmol). The mixture was sparged with nitrogen gas for 10minutes and sonicated for an additional 5 minutes. Palladium (II)acetate (0.019 g, 0.082 mmol) was added and the reaction mixture heatedat 100° C. under nitrogen for 16 hours. The mixture was then cooled toambient temperature then charged with additional cyclopropylboronic acid(0.227 g, 2.60 mmol), tricyclohexylphosphine tetrafluoroborate (0.070 g,0.19 mmol) and palladium(II) acetate (0.021 g, 0.094 mmol). The mixturewas heated to 100° C. and stirred for an additional 24 hours. Thesolution was then cooled to ambient temperature and filtered throughdiatomaceous earth with ethyl acetate. The solution was concentrated invacuo and purified by column chromatography (0% to 20% ethyl acetate inhexanes) to afford the title compound (0.173 g, 25%): ¹H NMR (300 MHz,CDCl₃) δ 7.38 (d, J=8.4 Hz, 1H), 6.51 (d, J=12.7 Hz, 1H), 4.04 (t, J=6.2Hz, 2H), 2.15-2.07 (m, 2H), 2.02-1.95 (m, 1H), 1.88-1.61 (m, 7H), 1.57(s, 9H), 1.43-1.31 (m, 2H), 0.92-0.86 (m, 2H), 0.66-0.61 (m, 2H).

Step 3. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-(2-(4,4-difluorocyclohexyl)-ethoxy)-2-fluorobenzamide

To a solution of tert-butyl5-chloro-4-(2-(4,4-difluorocyclohexyl)ethoxy)-2-fluorobenzoate (0.167 g,0.42 mmol) in anhydrous dichloromethane (1 mL) was added trifluoroaceticacid (0.50 mL) and the mixture was stirred at ambient temperature for 1hour. The solution was then concentrated in vacuo. The crude solid wascarried directly to the next step without further purification: MS (ES−)m/z 341.3 (M−1).

The crude acid was dissolved in anhydrous dichloromethane (11 mL). Tothis solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.124 g, 0.64 mmol) and 4-dimethylaminopyridine (0.119 g,0.98 mmol), and the solution was stirred at ambient temperature for 5minutes. Azetidine-1-sulfonamide (0.09 g, 0.69 mmol) was added to thereaction mixture and stirred for 16 hours. The reaction mixture wasdiluted with ethyl acetate (25 mL) and washed with 5% aqueoushydrochloric acid (2×50 mL) and water (50 mL); and the combined aqueouslayers were extracted with ethyl acetate (2×50 mL). The combined organiclayers were then washed with brine (50 mL), dried with anhydrous sodiumsulfate; filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (0% to 30% ethyl acetate in hexanes) to afford thetitle compound (0.05 g, 25% in two steps): ¹H NMR (300 MHz, CDCl₃) δ8.65 (d, J=16.0 Hz, 1H), 7.60 (d, J=9.1 Hz, 1H), 6.59 (d, J=14.3 Hz,1H), 4.25 (t, J=7.5 Hz, 4H), 4.09 (t, J=6.2 Hz, 2H), 2.35-2.22 (m, 2H),2.17-1.99 (m, 2H), 1.92-1.28 (m, 8H), 1.45-1.28 (m, 2H), 0.97-0.85 (m,2H), 0.70-0.65 (m, 2H); MS (ES−) m/z 459.2 (M−1).

Example 171 Synthesis of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(trifluoromethyl)-cyclopropyl)methoxy)benzamide

Following the procedure as described in Example 165 and makingvariations as required to replaceN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclopentyl)-methoxy)benzamidewith5-chloro-2-fluoro-N-(methylsulfonyl)-4-((1-(trifluoromethyl)-cyclopropyl)-methoxy)benzamide.Purification by reverse-phase preparative HPLC to yield the titlecompound (0.047 g, 19%): ¹H NMR (300 MHz, DMSO-d₆) 11.94 (br s, 1H),7.14 (d, J=8.3 Hz, 1H), 6.96 (d, J=12.9 Hz, 1H), 4.23 (s, 2H), 3.31 (s,3H), 2.09-2.00 (m, 1H), 1.16-1.11 (m, 2H), 1.07-1.02 (m, 2H), 0.93-0.86(m, 2H), 0.72-0.66 (m, 2H); MS (ES−) m/z 394.1 (M−1).

Example 172 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-methylcyclohexyl)methoxy)benzamide

Step 1. Preparation of tert-butyl5-chloro-2-fluoro-4-((1-methylcyclohexyl)-methoxy)benzoate

To a solution of (1-methylcyclohexyl)methanol (4.98 g, 38.80 mmol) andtert-butyl 5-chloro-2,4-difluorobenzoate (20.67 g, 83.10 mmol) inanhydrous dimethylsulfoxide (80 mL) was added cesium carbonate (25.14 g,77.20 mmol). The mixture was heated to 70° C. and stirred for 16 hours.The mixture was then cooled to ambient temperature, filtered through apad of diatomaceous earth and the solid was washed with ethyl acetate.The combined organic layers were washed with water and brine; dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography (0% to 10% ethyl acetatein hexanes) to afford the title compound (6.26 g, 44%): ¹H NMR (300 MHz,CDCl₃) δ 7.87 (d, J=7.7 Hz, 1H), 6.62 (d, J=12.2 Hz, 1H), 3.70 (s, 2H),1.57 (s, 9H), 1.52-1.31 (m, 10H), 1.08 (s, 3H).

Step 2. Preparation of5-cyclopropyl-2-fluoro-4-((1-methylcyclohexyl)methoxy)benzoic acid

To a solution of tert-butyl5-chloro-2-fluoro-4-((1-methylcyclohexyl)methoxy)benzoate (1.63 g, 4.6mmol) in toluene-water (v/v 20:1, 21 mL) was added tribasic potassiumphosphate (4.37 g, 20.60 mmol), cyclopropylboronic acid (0.581 g, 6.80mmol) and tricyclohexylphosphine tetrafluoroborate (0.168 g, 0.46 mmol).The mixture was sonicated for 5 minutes, and then sparged with nitrogenfor 10 minutes; palladium acetate (0.053 g, 0.23 mmol) was added and thereaction mixture was heated to 100° C. and stirred for 16 hours under anitrogen atmosphere. The reaction mixture was cooled to ambienttemperature and poured into water. The aqueous layer was separated andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was dissolved in anhydrousdichloromethane (8 mL) and trifluoroacetic acid (4 mL) was added. Themixture was stirred at ambient temperature for 3 hours and thenconcentrated in vacuo. The crude solid obtained was triturated withhexanes to provide the title compound (0.62 g, 44%): ¹H NMR (300 MHz,DMSO-d₆) δ 12.80 (br s, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.92 (d, J=13.2 Hz,1H), 3.79 (s, 2H), 2.06-1.96 (m, 1H), 1.48-1.17 (m, 10H), 1.04 (s, 3H),0.92-0.86 (m, 2H), 0.61-0.56 (m, 2H).

Step 3. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-methylcyclohexyl)methoxy)benzamide

To a solution of5-cyclopropyl-2-fluoro-4-((1-methylcyclohexyl)methoxy)benzoic acid(0.152 g, 0.50 mmol) in anhydrous dichloromethane (12 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.150 g,0.78 mmol) and 4-dimethylaminopyridine

(0.140 g, 1.10 mmol). The reaction mixture was stirred at ambienttemperature for 10 minutes, and then azetidine-1-sulfonamide (0.106 g,0.78 mmol) was added to the reaction mixture and stirred for 16 hours.The reaction mixture was poured into 5% aqueous hydrochloric acid, thelayers separated and the aqueous layer extracted with dichloromethane(3×20 mL). The combined organic layers were washed with water (20 mL)and brine (20 mL); dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatography(10% to 25% ethyl acetate in hexanes) to afford the title compound (0.15g, 71%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.60 (br s, 1H), 7.15 (d, J=8.3Hz, 1H), 6.98 (d, J=13.0 Hz, 1H), 4.04 (t, J=7.7 Hz, 4H), 3.80 (s, 2H),2.14-1.98 (m, 3H), 1.49-1.23 (m, 10H), 1.04 (s, 3H), 0.93-0.86 (m, 2H),0.70-0.65 (m, 2H); MS (ES−) m/z 423.2 (M−1).

Example 173 Synthesis of5-cyclopropyl-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)-4-((1-methylcyclohexyl)methoxy)benzamide

Following the procedure as described in EXAMPLE 172 step 3 and makingvariations as required to replace azetidine-1-sulfonamide with3-fluoroazetidine-1-sulfonamide, the title compound was obtained (0.14g, 58%): ¹H NMR (300 MHz, CDCl₃) δ 8.71 (d, J=17.0 Hz, 1H), 7.61 (d,J=9.1 Hz, 1H), 6.59 (d, J=14.5 Hz, 1H), 5.37-5.18 (m, 1H), 4.53-4.34 (m,4H), 3.72 (s, 2H), 2.09-1.99 (m, 1H) 1.55-1.25 (m, 10H), 1.09 (s, 3H),0.97-0.90 (m, 2H), 0.69-0.63 (m, 2H); MS (ES−) m/z 441.2 (M−1).

Example 173 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(spiro[2.5]octan-1-ylmethoxy)benzamide

To a solution of spiro[2.5]octan-1-ylmethanol (prepared according toHuang and Forsyth, Tetrahedron 1997, 53, 16341) (0.40 g, 2.87 mmol) inanhydrous dimethylsulfoxide (5 mL) was added potassium tert-butoxide(0.81 g, 7.24 mmol) and the reaction mixture was stirred for 30 minutesat ambient temperature. To this reaction mixture was addedN-(azetidin-1-ylsulfonyl)-5-chloro-2,4-difluorobenzamide (0.90 g, 2.89mmol) and stirred for 2 hours. The mixture was poured into 1 M aqueoushydrochloric acid, the layers were separated and the aqueous layer wasextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water and brine; dried over anhydrous sodium sulfate;filtered and concentrated in vacuo. The residue was purified by columnchromatography (0% to 30% ethyl acetate in hexanes) to afford the titlecompound (0.49 g, 39%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.81 (br s, 1H),7.78 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.5 Hz, 1H), 4.35-4.31 (dd, J=10.9,6.3 Hz, 1H), 4.04 (t, J=7.7 Hz, 5H), 2.17 (q, J=7.7 Hz, 2H), 1.77-0.94(m, 11H), 0.57-0.55 (dd, J=8.5, 4.3 Hz, 1H), 0.30 (t, J=4.7 Hz, 1H); MS(ES−) m/z 429.20 (M−1).

Example 174 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-1-ylmethoxy)benzamide

Following the procedure as described in Example 165 and makingvariations as required to replaceN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzamidewith N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(spiro[2.5]octan1-ylmethoxy)benzamide, the title compound was obtained (0.03 g, 7%) as acolorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.67 (br s, 1H), 7.58 (d,J=9.1 Hz, 1H), 6.58 (d, J=14.4 Hz, 1H), 4.24 (t, J=7.7 Hz, 5H), 3.86 (t,J=9.6 Hz, 1H), 2.26 (q, J=7.7 Hz, 2H), 2.15-2.05 (m, 1H), 1.79-1.18 (m,10H), 1.14-1.04 (m, 1H), 0.96-0.92 (m, 2H), 0.77-0.58 (m, 3H), 0.28 (t,J=5.0 Hz, 1H); MS (ES−) m/z 435.2 (M−1).

Example 175 Synthesis of4-(adamantan-2-yloxy)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluorobenzamide

Step 1. Preparation of tert-butyl4-(adamantan-2-yloxy)-5-chloro-2-fluorobenzoate

To a solution of 2-adamantanol (3.09 g, 20.26 mmol) in anhydrousdimethylsulfoxide (40 mL) was added tert-butyl5-chloro-2,4-difluorobenzoate (6.56 g, 26.38 mmol) and cesium carbonate(13.20 g, 40.51 mmol), and the reaction mixture was heated at 70° C. for16 hours. The solution was then cooled to ambient temperature andcharged with an additional portion of 2-adamantanol (0.51 g, 3.34 mmol)and the reaction mixture was heated at 70° C. for an additional 24hours. This process was repeated twice by addition of 2-adamantanol(0.49 g, 3.21 mmol) and (0.51 g, 3.31 mmol) respectively over anadditional 48 hours. The mixture was cooled to ambient temperature anddiluted with water (300 mL) and extracted with ethyl acetate (4×100 mL).The combined organic layers were washed with water (100 mL) and brine(100 mL); dried over anhydrous sodium sulfate, filtered and concentratedin vacuo. The residue was recrystallized from hexanes and thentriturated with methanol to give the title compound (1.63 g, 16%): ¹HNMR (300 MHz, CDCl₃) δ 7.88 (d, J=7.8 Hz, 1H), 6.62 (d, J=12.5 Hz, 1H),4.49 (br s, 1H), 2.20-2.10 (m, 4H), 1.99-1.68 (m, 10H), 1.57 (s, 9H).

Step 2. Preparation of4-(adamantan-2-yloxy)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluorobenzamide

To a solution of tert-butyl4-(adamantan-2-yloxy)-5-chloro-2-fluorobenzoate in toluene-water (v/v20:1, 20 mL) was added cyclopropylboronic acid (0.57 g, 6.65 mmol) andtribasic potassium phosphate (4.10 g, 19.31 mmol). The mixture was thensparged with argon for 5 minutes and was then charged withtricyclohexylphosphine tetrafluoroborate (0.33 g, 0.90 mmol) andpalladium acetate (0.11 g, 0.47 mmol) and the reaction mixture washeated at 110° C. for 16 hours. The reaction mixture was cooled toambient temperature, filtered through a pad of diatomaceous earth andwashed with ethyl acetate, concentrated in vacuo. to give the crudeproduct: ¹H NMR (300 MHz, CDCl₃) δ 7.40 (d, J=8.5 Hz, 1H), 6.49 (d,J=12.9 Hz, 1H), 4.45 (br s, 1H), 2.18-2.04 (m, 6H), 1.94-1.81 (m, 9H),1.56 (s, 9H), 0.92-0.86 (m, 2H), 0.67-0.62 (m, 2H). The crude productwas dissolved in anhydrous dichloromethane (6 mL), and trifluoroaceticacid (3 mL) was added. The reaction mixture was stirred for 2 hours atambient temperature; concentrated in vacuo to give the crude carboxylicacid (1.02 g, 72%): ¹H NMR (300 MHz, CDCl₃) δ 7.54 (d, J=8.6 Hz, 1H),6.56 (d, J=13.2 Hz, 1H), 4.49 (br s, 1H), 2.20-1.70 (m, 12H), 1.62-1.53(m, 1H), 1.34-1.17 (m, 2H), 0.96-0.90 (m, 2H), 0.69-0.64 (m, 2H). Thecrude carboxylic acid (0.34 g, 1.03 mmol) was dissolved in anhydrousdichloromethane (27 mL) and added1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.30 g,1.56 mmol) and 4-dimethylaminopyridine (0.30 g, 2.42 mmol), afterstirring for 5 minutes, azetidine-1-sulfonamide (0.23 g, 1.69 mmol) wasadded and stirring was continued for 16 hours at ambient temperature.The mixture was then poured into a 5% aqueous solution of hydrochloricacid, the layers separated and the aqueous layer extracted withdichloromethane (3×20 mL). The combined organic layers were then washedwith distilled water (20 mL) and brine (20 mL), dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography (0% to 30% ethyl acetate in hexanes)to afford the title compound (0.11 g, 24%): ¹H NMR (300 MHz, CDCl₃) δ8.65 (d, J=16.5 Hz, 1H), 7.63 (d, J=9.3 Hz, 1H), 6.56 (d, J=14.8 Hz,1H), 4.53-4.48 (m, 1H), 4.25 (t, J=7.74 Hz, 4H), 2.32-2.07 (m, 7H),2.01-1.79 (m, 8H), 1.62-1.58 (m, 2H), 0.97-0.90 (m, 2H), 0.71-0.65 (m,2H); MS (ES−) m/z 447.2 (M−1).

Example 176 Synthesis of4-(adamantan-2-yloxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 175 step 2 and makingvariations as required to replace azetidine-1-sulfonamide withcyclopropanesulfonamide, the title compound was obtained (0.15 g, 37%):¹H NMR (300 MHz, CDCl₃) δ 8.69 (d, J=16.1 Hz, 1H), 7.60 (d, J=9.2 Hz,1H), 6.55 (d, J=14.8 Hz, 1H), 4.53-4.48 (m, 1H), 3.14-3.05 (m, 1H),2.20-2.05 (m, 5H), 2.00 (s, 1H), 1.97-1.78 (m, 7H), 1.61-1.57 (m, 2H),1.47-1.41 (m, 2H), 1.17-1.10 (m, 2H), 0.96-0.90 (m, 2H), 0.69-0.63 (m,2H); MS (ES−) m/z 432.2 (M−1).

Example 177 Synthesis of4-(adamantan-2-yloxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 175 step 2 and makingvariations as required to replace cyclopropanesulfonamide withmethanesulfonamide, the title compound was obtained (0.20 g, 43%): ¹HNMR (300 MHz, CDCl₃) d 8.70 (d, J=16.3 Hz, 1H), 7.61 (d, J=9.2 Hz, 1H),6.55 (d, J=14.8 Hz, 1H), 4.53-4.47 (m, 1H), 3.41 (s, 3H), 2.20-1.79 (m,12H), 1.09 (s, 3H), 0.98-0.91 (m, 2H), 0.69-0.64 (m, 2H); MS (ES−) m/z406.2 (M−1).

Example 178 Synthesis of5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of tert-butyl5-chloro-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoate

A mixture of (4,4-difluoro-1-methylcyclohexyl)methanol (3.05 g, 18.56mmol)(PCT Int. Appl., WO2012025857, 2012), cesium carbonate (12.09 g,37.12 mmol), and tert-butyl 5-chloro-2,4-difluorobenzoate (6.0 g, 24.13mmol) in dimethylsulfoxide (70 mL) was stirred at 70° C. for 16 hours,cooled to ambient temperature and diluted with ethyl acetate (150 mL);washed with water (2×300 mL), brine (150 mL); dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. Purification ofthe residue by column chromatography eluting with a gradient of ethylacetate in hexanes (0-5%) afforded the title compound (3.69 g, 51%) ascolorless oil: MS (ES+) m/z 393.1 (M+1).

Step 2. Preparation of tert-butyl5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)-methoxy)-2-fluorobenzoate

Following the procedure as described in Example 158 step 3, and makingvariations as required to replace tert-butyl5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoatewith tert-butyl5-chloro-4-((4,4-difluoro-1-methylcyclohexyl)-methoxy)-2-fluorobenzoate,the title compound was obtained as colorless oil (3.69 g, 99%): MS (ES+)m/z 399.2 (M+23).

Step 3. Preparation of5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoicacid

Following the procedure as described in Example 158 step 4, and makingvariations as required to replace tert-butyl5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoatewith tert-butyl5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoate,the title compound was obtained as a colorless solid (2.74 g, 86%): MS(ES+) m/z 343.2 (M+1).

Step 4. Preparation of5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoicacid with5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoicacid, the title compound was obtained as a colorless solid (0.144 g,53%): ¹H NMR (300 MHz, CDCl₃) δ8.79-8.65 (m, 1H), 7.68-7.56 (m, 1H),6.64-6.53 (m, 1H), 3.76 (s, 2H), 3.42 (s, 3H), 2.08-1.73 (m, 7H),1.69-1.58 (m, 2H), 1.17 (s, 3H), 1.00-0.89 (m, 2H), 0.69-0.60 (m, 2H);MS (ES+) m/z 420.1 (M+1).

Example 179 Synthesis of5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoicacid with5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoicacid and to replace methanesulfonamide with 2-methoxyethanesulfonamide,the title compound was obtained (0.162 g, 55%) as a colorless solid: ¹HNMR (300 MHz, CDCl₃) δ 8.72-8.57 (m, 1H), 7.68-7.55 (m, 1H), 6.63-6.51(m, 1H), 3.94-3.70 (m, 6H), 3.31 (s, 3H), 2.08-1.75 (m, 7H), 1.68-1.58(m, 2H), 1.17 (s, 3H), 0.99-0.89 (m, 2H), 0.70-0.60 (m, 2H); MS (ES+)m/z 464.1 (M+1).

Example 180 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4,4-difluoro-1-methylcyclohexyl)-methoxy)-2-fluorobenzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoicacid with5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoicacid and to replace methanesulfonamide with cyclopropanesulfonamide, thetitle compound was obtained (0.17 g, 61%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ 8.75-8.62 (m, 1H), 7.68-7.58 (m, 1H), 6.63-6.50 (m,1H), 3.76 (s, 2H), 3.15-3.05 (m, 1H), 2.09-1.74 (m, 7H), 1.69-1.57 (m,2H), 1.50-1.41 (m, 2H), 1.22-1.09 (m, 5H), 1.00-0.89 (m, 2H), 0.70-0.60(m, 2H); MS (ES+) m/z 446.1 (M+1).

Example 181 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)-methoxy)-2-fluorobenzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoicacid with5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoicacid and to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained (0.17 g, 56%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ 8.72-8.59 (m, 1H), 7.69-7.61 (m, 1H), 6.64-6.52 (m,1H), 4.31-4.19 (m, 4H), 3.76 (s, 2H), 2.35-2.20 (m, 2H), 2.08-1.73 (m,7H), 1.69-1.58 (m, 2H), 1.17 (s, 3H), 0.99-0.89 (m, 2H), 0.71-0.61 (m,2H); MS (ES+) m/z 461.1 (M+1).

Example 182 Synthesis of5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluoro-N-(N-methylsulfamoyl)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoicacid with5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoicacid and to replace methanesulfonamide with (methylsulfamoyl)amine, thetitle compound was obtained (0.13 g, 47%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ 8.77-8.62 (m, 1H), 7.66-7.56 (m, 1H), 6.65-6.51 (m,1H), 5.30-5.18 (m, 1H), 3.76 (s, 2H), 2.82-2.71 (m, 3H), 2.09-1.73 (m,7H), 1.69-1.59 (m, 2H), 1.17 (s, 3H), 1.01-0.90 (m, 2H), 0.70-0.61 (m,2H); MS (ES+) m/z 435.1 (M+1).

Example 183 Synthesis of5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoicacid with5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoicacid and to replace methanesulfonamide with3-fluoroazetidine-1-sulfonamide, the title compound was obtained (0.06g, 20%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.81-8.63 (m,1H), 7.70-7.58 (m, 1H), 6.66-6.50 (m, 1H), 5.45-5.13 (m, 1H), 4.59-4.29(m, 4H), 3.77 (s, 2H), 2.09-1.74 (m, 7H), 1.69-1.60 (m, 2H), 1.17 (s,3H), 1.01-0.89 (m, 2H), 0.71-0.60 (m, 2H); MS (ES+) m/z 479.1 (M+1).

Example 184 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-isopropoxyethyl)-sulfonyl)benzamide

Following the procedure as described in Example 50 step 5 and makingvariations as required to replace methanesulfonamide with2-methoxyethane-1-sulfonamide, the title compound was obtained as acolorless solid (0.155 g, 36%): ¹H NMR (300 MHz, CDCl₃) δ 8.71-8.55 (m,1H), 7.64-7.55 (m, 1H), 6.62-6.50 (m, 1H), 3.94-3.72 (m, 4H), 3.62-3.48(m, 3H), 2.11-1.97 (m, 4H), 1.86-1.64 (m, 12H), 1.09-0.99 (m, 6H),0.99-0.88 (m, 2H), 0.70-0.59 (m, 2H); MS (ES+) m/z 494.2 (M+1).

Example 185 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-methoxypropyl)-sulfonyl)benzamide

Following the procedure as described in Example 50 step 5, and makingvariations as required to replace methanesulfonamide with3-methoxypropane-1-sulfonamide, the title compound was obtained as acolorless solid (0.15 g, 36%): ¹H NMR (300 MHz, CDCl₃) δ 8.67-8.54 (m,1H), 7.62-7.54 (m, 1H), 6.61-6.51 (m, 1H), 3.72-3.63 (m, 2H), 3.56 (s,2H), 3.53-3.46 (m, 2H), 3.31 (s, 3H), 2.19-2.00 (m, 6H), 1.84-1.65 (m,12H), 0.99-0.89 (m, 2H), 0.70-0.61 (m, 2H); MS (ES−) m/z 478.3 (M−1).

Example 186 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-((2-ethoxyethyl)sulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 50 step 5, and makingvariations as required to replace methanesulfonamide with2-ethoxyethanesulfonamide, the title compound was obtained as acolorless solid (0.114 g, 24%): ¹H NMR (300 MHz, CDCl₃) δ 8.67-8.54 (m,1H), 7.62-7.54 (m, 1H), 6.61-6.51 (m, 1H), 3.72-3.63 (m, 2H), 3.56 (s,2H), 3.53-3.46 (m, 2H), 3.31 (s, 3H), 2.19-2.00 (m, 6H), 1.84-1.65 (m,12H), 0.99-0.89 (m, 2H), 0.70-0.61 (m, 2H); MS (ES−) m/z 478.3 (M−1).

Example 187 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((tetrahydrofuran-3-yl)sulfonyl)benzamide

Following the procedure as described in Example 38 step 4 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide and to replacemethanesulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride, thetitle compound was obtained as a colorless solid (0.14 g, 28%): ¹H NMR(300 MHz, CDCl₃) δ8.72-8.60 (m, 1H), 7.60-7.53 (m, 1H), 6.63-6.53 (m,1H), 4.62-4.48 (m, 1H), 4.33-4.23 (m, 1H), 4.16-3.82 (m, 3H), 3.56 (s,2H), 2.58-2.44 (m, 1H), 2.42-2.26 (m, 1H), 2.10-1.99 (m, 4H), 1.84-1.66(m, 12H), 1.00-0.89 (m, 2H), 0.70-0.61 (m, 2H); MS (ES+) m/z 478.1(M+1).

Example 188 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((tetrahydro-2H-pyran-4-yl)sulfonyl)benzamide

Following the procedure as described in Example 38 step 4 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide and to replacemethanesulfonyl chloride with tetrahydro-2H-pyran-4-sulfonyl chloride,the title compound was obtained as a colorless solid (0.15 g, 30%): ¹HNMR (300 MHz, CDCl₃) δ8.55-8.44 (m, 1H), 7.60-7.52 (m, 1H), 6.62-6.52(m, 1H), 4.17-3.90 (m, 3H), 3.56 (s, 2H), 3.47-3.36 (m, 2H), 2.12-1.95(m, 8H), 1.84-1.65 (m, 12H), 1.00-0.90 (m, 2H), 0.71-0.58 (m, 2H); MS(ES+) m/z 492.21 (M+1).

Example 189 Synthesis of4-(adamantan-1-ylmethoxy)-N-(cyclobutylsulfonyl)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 38 step 4 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide and to replacemethanesulfonyl chloride with cyclobutanesulfonyl chloride, the titlecompound was obtained as a colorless solid (0.05 g, 10%): ¹H NMR (300MHz, CDCl₃) δ8.57-8.44 (m, 1H), 7.60-7.52 (m, 1H), 6.61-6.48 (m, 1H),4.61-4.46 (m, 1H), 3.55 (s, 2H), 2.74-2.56 (m, 2H), 2.45-2.29 (m, 2H),2.12-1.97 (m, 6H), 1.84-1.64 (m, 12H), 0.99-0.88 (m, 2H), 0.71-0.58 (m,2H); MS (ES+) m/z 462.2 (M+1).

Example 190 Synthesis of4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1.5-chloro-4-(cyclohexylmethoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with cyclohexylmethanol,the title compound was obtained as a colorless solid (0.53 g, 39%): MS(ES−) m/z 362.2, 364.2 (M−1).

Step 2. Preparation of4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 49 and making variationsas required to replace4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamidewith5-chloro-4-(cyclohexylmethoxy)-2-fluoro-N-(methylsulfonyl)benzamide, thetitle compound was obtained as a colorless solid (0.19 g, 14%): ¹H NMR(300 MHz, CDCl₃) δ8.77-8.66 (m, 1H), 7.61-7.52 (m, 1H), 6.62-6.52 (m,1H), 3.86-3.78 (m, 2H), 3.41 (s, 3H), 2.12-1.99 (m, 1H), 1.95-1.66 (m,6H), 1.40-1.03 (m, 5H), 0.99-0.89 (m, 2H), 0.69-0.61 (m, 2H); MS (ES−)m/z 368.3 (M−1).

Example 191 Synthesis of4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)benzamide

Step 1. Preparation of 5-chloro-4-(cyclohexylmethoxy)-2-fluorobenzoicacid

Following the procedure as described in Example 158 step 1, and makingvariations as required to replace(1-(trifluoromethyl)cyclohexyl)-methanol with cyclohexylmethanol, thetitle compound was obtained as colorless solid (41.16 g, 92%) containingo-substituted regioisomer, which was used for next step without furtherpurification: MS (ES−) m/z 285.2, 287.2 (M−1).

Step 2. Preparation of tert-butyl5-chloro-4-(cyclohexylmethoxy)-2-fluorobenzoate

Following the procedure as described in Example 158 step 2 and makingvariations as required to replace5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)benzoic acidwith 5-chloro-4-(cyclohexylmethoxy)-2-fluorobenzoic acid, the titlecompound was obtained as a colorless oil (15.37 g, 43%): MS (ES+) m/z381.2 (M+39).

Step 3. Preparation of tert-butyl4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoate

Following the procedure as described in Example 158 step 3 and makingvariations as required to replace tert-butyl5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoatewith tert-butyl 5-chloro-4-(cyclohexylmethoxy)-2-fluorobenzoate, thetitle compound was obtained as colorless oil (13.73 g, 88%): MS (ES+)m/z 387.2 (M+39).

Step 4. Preparation of4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid

Following the procedure as described in Example 158 step 4 and makingvariations as required to replace tert-butyl5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoatewith tert-butyl 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoate,the title compound was obtained as a colorless solid (6.64 g, 58%): MS(ES−) m/z 291.3 (M−1).

Step 5. Preparation of4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid with 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid andto replace methanesulfonamide with 3-fluoroazetidine-1-sulfonamide, thetitle compound was obtained (0.09 g, 35%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ8.80-8.64 (m, 1H), 7.62-7.52 (m, 1H), 6.64-6.52 (m,1H), 5.45-5.12 (m, 1H), 4.59-4.31 (m, 4H), 3.89-3.76 (m, 2H), 2.13-1.99(m, 1H), 1.96-1.68 (m, 6H), 1.42-1.03 (m, 5H), 1.00-0.89 (m, 2H),0.72-0.62 (m, 2H); MS (ES+) m/z 429.2 (M+1).

Example 192 Synthesis of(S)-4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-hydroxypyrrolidin-1-yl)sulfonyl)benzamide

Step 1. Preparation of(S)-4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-((4-methoxybenzyl)oxy)pyrrolidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid with 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid andto replace methanesulfonamide with(3S)-3-((4-methoxybenzyl)oxy)-cyclopentane-1-sulfonamide, the titlecompound was obtained (0.22 g, 56%) as a colorless solid: MS (ES+) m/z561.2 (M+1);

Step 2. Preparation of(S)-4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-hydroxypyrrolidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 124 step 3 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-chloro-2-fluoro-N—(((S)-3-((4-methoxybenzyl)oxy)pyrrolidin-1-yl)sulfonyl)benzamidewith(S)-4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-((4-methoxybenzyl)oxy)pyrrolidin-1-yl)sulfonyl)benzamide,the title compound was obtained as colorless solid (0.14 g, 78%): ¹H NMR(300 MHz, CDCl₃) δ 8.86-8.76 (m, 1H), 7.58-7.46 (m, 1H), 6.63-6.48 (m,1H), 4.55-4.35 (m, 1H), 3.92-3.77 (m, 3H), 3.71-3.59 (m, 3H), 2.48 (brs, 1H), 2.13-1.96 (m, 3H), 1.95-1.67 (m, 6H), 1.42-1.02 (m, 5H),0.98-0.85 (m, 2H), 0.69-0.57 (m, 2H); MS (ES+) m/z 441.1 (M+1).

Example 193 Synthesis of4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)-sulfonyl)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid with 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid andto replace methanesulfonamide with 2-methoxyethanesulfonamide, the titlecompound was obtained (0.16 g, 40%) as a colorless solid: ¹H NMR (300MHz, CDCl₃) δ8.70-8.59 (m, 1H), 7.58-7.51 (m, 1H), 6.61-6.51 (m, 1H),3.90-3.74 (m, 6H), 3.31 (s, 3H), 2.11-1.99 (m, 1H), 1.95-1.67 (m, 6H),1.41-1.04 (m, 5H), 0.98-0.89 (m, 2H), 0.69-0.61 (m, 2H); MS (ES−) m/z412.3 (M−1);

Example 194 Synthesis ofN-(azetidin-1-ylsulfonyl)-4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in preparation of Example 158 step5, and making variations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid with 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid andto replace methanesulfonamide with azetidine-1-sulfonamide, the titlecompound was obtained (0.13 g, 47%) as a colorless solid: ¹H NMR (300MHz, CDCl₃) δ 8.71-8.61 (m, 1H), 7.62-7.55 (m, 1H), 6.62-6.51 (m, 1H),4.30-4.18 (m, 4H), 3.86-3.76 (m, 2H), 2.34-2.20 (m, 2H), 2.13-2.00 (m,1H), 1.96-1.67 (m, 6H), 1.41-1.02 (m, 5H), 0.99-0.87 (m, 2H), 0.72-0.61(m, 2H); MS (ES−) m/z 409.3 (M−1).

Example 195 Synthesis of4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-hydroxyethyl)-sulfonyl)benzamide

Following the procedure as described in Example 121 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)-sulfonyl)benzamidewith4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)-sulfonyl)benzamide,the title compound was obtained as colorless solid (0.03 g, 14%): ¹H NMR(300 MHz, CDCl₃) δ8.77-8.65 (m, 1H), 7.60-7.49 (m, 1H), 6.63-6.51 (m,1H), 4.19-4.09 (m, 2H), 3.86-3.74 (m, 4H), 2.59-2.49 (m, 1H), 2.10-1.98(m, 1H), 1.94-1.68 (m, 6H), 1.39-1.04 (m, 5H), 0.99-0.90 (m, 2H),0.70-0.61 (m, 2H); MS (ES−) m/z 398.3 (M−1).

Example 196 Synthesis of4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluoro-N-(N-methylsulfamoyl)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid with 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid andto replace methanesulfonamide with (methylsulfamoyl)amine, the titlecompound was obtained (0.13 g, 25%) as a colorless solid: ¹H NMR (300MHz, CDCl₃) δ8.76-8.65 (m, 1H), 7.57-7.50 (m, 1H), 6.62-6.52 (m, 1H),5.31-5.22 (m, 1H), 3.86-3.78 (m, 2H), 2.79-2.74 (m, 3H), 2.11-1.99 (m,1H), 1.95-1.65 (m, 6H), 1.41-1.03 (m, 5H), 0.98-0.89 (m, 2H), 0.69-0.61(m, 2H); MS (ES−) m/z 383.3 (M−1).

Example 197 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-dimethylcyclohexyl)-methoxy)-2-fluorobenzamide

Step 1. Preparation of tert-butyl5-chloro-4-((4,4-dimethyl-cyclohexyl)methoxy)-2-fluorobenzoate

To a cooled to 0° C. solution of 4,4-dimethylcyclohexanecarbaldehyde(1.42 g, 10.13 mmol) (PCT Int. Appl., WO 2012087519, 2012) in drymethanol (22 mL) was added sodium borohydride (0.766 g, 20.25 mmol). Thereaction mixture was stirred at 0° C. for 1 hour, and then concentratedin vacuo. The residue was diluted with saturated aqueous ammoniumchloride solution (25 mL) and extracted with ethyl acetate (3×85 mL).The combined organic layers were washed with brine (100 mL), dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo toafford the product (1.23 g) as a colorless oil. The oil was dissolved indimethylsulfoxide (30 mL) and cesium carbonate (5.64 g, 17.3 mmol) wasadded followed by tert-butyl 5-chloro-2,4-difluorobenzoate (3.23 g,12.97 mmol). The mixture was stirred at 70° C. for 16 hours, then cooledto ambient temperature and diluted with ethyl acetate (150 mL). Themixture was washed with water (2×200 mL) and brine (150 mL); dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo.Purification of the residue by column chromatography (0-10% ethylacetate in hexanes) afforded the title compound (2.87 g, 89%) ascolorless oil: MS (ES+) m/z 371.1 (M+1).

Step 2. Preparation of tert-butyl5-cyclopropyl-4-((4,4-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate

Following the procedure as described in Example 158 step 3, and makingvariations as required to replace tert-butyl5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoatewith tert-butyl5-chloro-4-((4,4-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate, thetitle compound was obtained as a pale yellow oil (2.13 g, 73%): MS (ES+)m/z 399.2 (M+23).

Step 3. Preparation of5-cyclopropyl-4-((4,4-dimethylcyclohexyl)-methoxy)-2-fluorobenzoic acid

Following the procedure as described in Example 158 step 4, and makingvariations as required to replace tert-butyl5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoatewith tert-butyl5-cyclopropyl-4-((4,4-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate, thetitle compound was obtained as a colorless solid (0.356 g, 20%): MS(ES+) m/z 321.2 (M+1).

Step 4. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-dimethylcyclohexyl)-methoxy)-2-fluorobenzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid with5-cyclopropyl-4-((4,4-dimethylcyclohexyl)-methoxy)-2-fluorobenzoic acidand to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained (0.16 g, 51%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ8.71-8.58 (m, 1H), 7.64-7.56 (m, 1H), 6.64-6.52 (m,1H), 4.34-4.18 (m, 4H), 3.92-3.80 (m, 2H), 2.36-2.18 (m, 2H), 2.12-1.97(m, 1H), 1.87-1.66 (m, 3H), 1.51-1.19 (m, 6H), 1.01-0.84 (m, 8H),0.74-0.62 (m, 2H); MS (ES+) m/z 439.2 (M+1).

Example 198 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((3,3-dimethylcyclohexyl)methoxy)-2-fluorobenzamide

Step 1. Preparation of5-chloro-4-((3,3-dimethylcyclohexyl)-methoxy)-2-fluorobenzoic acid

Following the procedure as described in Example 158 step 1 and makingvariations as required to replace(1-(trifluoromethyl)cyclohexyl)methanol with(3,3-dimethylcyclohexyl)methanol (Jpn. Kokai Tokkyo Koho, 61158943,1986), the title compound was obtained as a pale yellow oil (2.74 g,100%) containing o-substituted regioisomer, which was used for next stepwithout further purification: MS (ES−) m/z 313.2 (M−1).

Step 2. tert-butyl5-chloro-4-((3,3-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate

Following the procedure as described in Example 158 step 2 and makingvariations as required to replace5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)benzoic acidwith 5-chloro-4-((3,3-dimethylcyclohexyl)methoxy)-2-fluorobenzoic acid,the title compound was obtained as pale yellow oil (3.20 g, 99%): MS(ES−) m/z 316.9 (M−54).

Step 3. Preparation of tert-butyl5-cyclopropyl-4-((3,3-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate

Following the procedure as described in Example 158 step 3 and makingvariations as required to replace tert-butyl5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoatewith tert-butyl5-chloro-4-((3,3-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate, thetitle compound was obtained as colorless oil (2.45 g, 75%): MS (ES+) m/z399.2 (M+23).

Step 4. Preparation of5-cyclopropyl-4-((3,3-dimethylcyclohexyl)-methoxy)-2-fluorobenzoic acid

Following the procedure as described in Example 158 step 4, and makingvariations as required to replace tert-butyl5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoatewith tert-butyl5-cyclopropyl-4-((3,3-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate, thetitle compound was obtained as a colorless solid (0.46 g, 22%): MS (ES−)m/z 319.3 (M−1).

Step 5. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((3,3-dimethylcyclohexyl)-methoxy)-2-fluorobenzamide

Following the procedure as described in Example 158 step 5 and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid with5-cyclopropyl-4-((3,3-dimethylcyclohexyl)-methoxy)-2-fluorobenzoic acidand to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained (0.12 g, 41%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ8.72-8.59 (m, 1H), 7.63-7.55 (m, 1H), 6.61-6.51 (m,1H), 4.34-4.16 (m, 4H), 3.86-3.70 (m, 2H), 2.34-2.20 (m, 2H), 2.13-2.00(m, 2H), 1.97-1.86 (m, 1H), 1.70-1.38 (m, 4H), 1.20-0.90 (m, 11H),0.72-0.63 (m, 2H); MS (ES+) m/z 439.2 (M+1).

Example 199/200 Synthesis oftrans-5-chloro-2-fluoro-4-((−5-fluoroadamantan-2-yl)oxy)-N-(methylsulfonyl)benzamide

andcis-5-chloro-2-fluoro-4-((−5-fluoroadamantan-2-yl)oxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with5-fluoroadamantan-2-ol (J. Am. Chem. Soc. 1986, 108, 1598;), twodiastereomers were obtained by silica gel chromatography: Data for thefirst diastereomer,trans-5-chloro-2-fluoro-4-((−5-fluoroadamantan-2-yl)oxy)-N-(methylsulfonyl)benzamide:a colorless solid (0.041 g, 2%): ¹H NMR (300 MHz, CDCl₃) δ8.74-8.61 (m,1H), 8.17-8.08 (m, 1H), 6.74-6.65 (m, 1H), 4.57-4.50 (m, 1H), 3.43 (s,3H), 2.43 (s, 2H), 2.30 (s, 1H), 2.19-2.07 (m, 2H), 2.06-1.92 (m, 6H),1.57-1.41 (m, 2H);

MS (ES−) m/z 418.2 (M−1), 420.2 (M−1). Data for the second diastereomer,cis-5-chloro-2-fluoro-4-((−5-fluoroadamantan-2-yl)oxy)-N-(methylsulfonyl)benzamide:a colorless solid (0.0044 g, 0.2%): ¹H NMR (300 MHz, CDCl₃) δ 8.73-8.60(m, 1H), 8.18-8.11 (m, 1H), 6.74-6.63 (m, 1H), 4.43-4.34 (m, 1H), 3.43(s, 3H), 2.53 (s, 2H), 2.41-2.25 (m, 3H), 1.98-1.65 (m, 8H); MS (ES−)m/z 418.2 (M−1), 420.2 (M−1).

Example 201 Synthesis of5-cyclopropyl-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 49 and making variationsas required to replace4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamidewith5-chloro-2-fluoro-4-((−5-fluoroadamantan-2-yl)oxy)-N-(methylsulfonyl)benzamide,the title compound was obtained as a colorless solid (0.008 g, 5%): ¹HNMR (300 MHz, CDCl₃) δ 8.77-8.63 (m, 1H), 7.66-7.58 (m, 1H), 6.61-6.50(m, 1H), 4.55-4.44 (m, 1H), 3.42 (s, 3H), 2.45 (s, 2H), 2.36-2.25 (m,1H), 2.17-1.92 (m, 9H), 1.54-1.43 (m, 2H), 1.02-0.88 (m, 2H), 0.72-0.59(m, 2H); MS (ES+) m/z 426.1 (M+1).

Example 202 Synthesis of:4-((adamantan-1-yloxy)methyl)-N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluorobenzamide

Following the procedure as described in Example 47 step 5 and makingvariations as required to replace mathanesulfonamide withazetidine-1-sulfonamide, the title compound was obtained as a colorlesssolid (0.04 g, 8%): ¹H NMR (300 MHz, CDCl₃) δ8.78-8.66 (m, 1H),8.09-8.03 (m, 1H), 7.56-7.47 (m, 1H), 4.60 (s, 2H), 4.32-4.20 (m, 4H),2.36-2.15 (m, 5H), 1.87-1.82 (m, 6H), 1.75-1.59 (m, 6H); MS (ES+) m/z457.1 (M+1).

Example 203 Synthesis of4-((adamantan-1-yloxy)methyl)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 49 and making variationsas required to replace4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamidewith4-((adamantan-1-yloxy)methyl)-N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluorobenzamide,the title compound was obtained as a colorless solid (0.135 g, 83%): ¹HNMR (300 MHz, CDCl₃) δ8.82-8.68 (m, 1H), 7.76-7.68 (m, 1H), 7.44-7.34(m, 1H), 4.72 (s, 2H), 4.33-4.18 (m, 4H), 2.35-2.15 (m, 5H), 1.90-1.60(m, 13H), 1.02-0.89 (m, 2H), 0.73-0.62 (m, 2H); MS (ES+) m/z 463.2(M+1).

Example 204 Synthesis of4-(adamantan-2-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of4-(adamantan-2-ylmethoxy)-5-chloro-2-fluorobenzoic acid

Following the procedure as described in preparation of Example 158 step1, and making variations as required to replace(1-(trifluoromethyl)cyclohexyl)methanol with adamantan-2-ylmethanol, thetitle compound was obtained as a colorless solid (3.79 g, 41%)containing o-substituted regioisomer, which was used for next stepwithout further purification: MS (ES+1) m/z 339.1, 341.1 (M+1).

Step 2. Preparation of tert-butyl4-(adamantan-2-ylmethoxy)-5-chloro-2-fluorobenzoate

Following the procedure as described in Example 158 step 2, and makingvariations as required to replace5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoicacid with 4-(adamantan-2-ylmethoxy)-5-chloro-2-fluorobenzoic acid, thetitle compound was obtained as a colorless oil (2.13. g, 48%): MS (ES−)m/z 393.2 (M−1).

Step 3. Preparation of tert-butyl4-(adamantan-2-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate

Following the procedure as described in Example 158 step 3, and makingvariations as required to replace tert-butyl5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoatewith tert-butyl 4-(adamantan-2-ylmethoxy)-5-chloro-2-fluorobenzoate, thetitle compound was obtained as colorless oil (1.99 g, 92%): MS (E+) m/z401.3 (M+1).

Step 4. Preparation of4-(adamantan-2-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid

Following the procedure as described in Example 158 step 4, and makingvariations as required to replace tert-butyl5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoatewith tert-butyl4-(adamantan-2-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate, the titlecompound was obtained as a colorless solid (0.79 g, 46%): MS (ES−) m/z343.3 (M−1).

Step 5. Preparation of4-(adamantan-2-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoicacid with 4-(adamantan-2-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid,the title compound was obtained as a colorless solid (0.16 g, 49%): ¹HNMR (300 MHz, CDCl₃) δ 8.78-8.66 (m, 1H), 7.60-7.51 (m, 1H), 6.70-6.57(m, 1H), 4.16-4.06 (m, 2H), 3.42 (s, 3H), 2.36-2.25 (m, 1H), 2.12-1.73(m, 13H), 1.69-1.60 (m, 2H), 0.98-0.89 (m, 2H), 0.70-0.60 (m, 2H); MS(ES−) m/z 420.3 (M−1).

Example 205 Synthesis of4-(adamantan-2-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)-sulfonyl)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoicacid with 4-(adamantan-2-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acidand to replace methanesulfonamide with 2-methoxyethanesulfonamide, thetitle compound was obtained (0.16 g, 40%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ8.73-8.59 (m, 1H), 7.60-7.48 (m, 1H), 6.69-6.56 (m,1H), 4.15-4.06 (m, 2H), 3.90-3.75 (m, 4H), 3.31 (s, 3H), 2.35-2.24 (m,1H), 2.10-1.73 (m, 13H), 1.69-1.59 (m, 2H), 0.98-0.87 (m, 2H), 0.68-0.60(m, 2H); MS (ES−) m/z 464.3 (M−1).

Example 206 Synthesis of4-(adamantan-2-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoicacid with 4-(adamantan-2-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acidand to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained (0.07 g, 26%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ8.72-8.62 (m, 1H), 7.60-7.54 (m, 1H), 6.67-6.59 (m,1H), 4.31-4.20 (m, 4H), 4.14-4.07 (m, 2H), 2.36-2.20 (m, 3H), 2.08-1.75(m, 13H), 1.70-1.60 (m, 2H), 0.97-0.89 (m, 2H), 0.71-0.63 (m, 2H); MS(ES−) m/z 461.3 (M−1).

Example 207 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith N-(azetidin-1-ylsulfonyl)-5-chloro-2,4-difluorobenzamide and toreplace adamantan-1-ylmethanol with spiro[2.5]octan-6-ylmethanol, thetitle compound was obtained as a colorless solid (0.61 g, 53%): ¹H NMR(300 MHz, CDCl₃) δ 8.70-8.57 (m, 1H), 8.17-8.09 (m, 1H), 6.76-6.66 (m,1H), 4.32-4.19 (m, 4H), 3.96-3.87 (m, 2H), 2.35-2.20 (m, 2H), 2.03-1.70(m, 5H), 1.39-1.20 (m, 2H), 1.02-0.86 (m, 2H), 0.38-0.16 (m, 4H); MS(ES+) m/z 431.1 (M+1), 433.1 (M+1).

Example 208 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide

Following the procedure as described in Example 49 and making variationsas required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide withN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide,the title compound was obtained as a colorless solid (0.39 g, 66%): ¹HNMR (300 MHz, CDCl₃) δ 8.74-8.59 (m, 1H), 7.64-7.54 (m, 1H), 6.64-6.52(m, 1H), 4.31-4.18 (m, 4H), 3.93-3.81 (m, 2H), 2.35-2.20 (m, 2H),2.13-2.00 (m, 1H), 1.99-1.72 (m, 5H), 1.40-1.20 (m, 2H), 1.02-0.85 (m,4H), 0.73-0.61 (m, 2H), 0.37-0.14 (m, 4H); MS (ES+1) m/z 437.2 (M+1).

Example 209 Synthesis of5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide

Step 1. Preparation of5-chloro-N-(cyclopropylsulfonyl)-2,4-difluorobenzamide

A mixture of 5-chloro-2,4-difluorobenzoic acid (10.0 g, 51.93 mmol) and1,1′-carbonyldiimidazole (10.11 g, 62.32 mmol) was stirred at reflux for2 hours, cooled to ambient temperature, and cyclopropanesulfonamide(7.55 g, 62.32 mmol) was added. The reaction mixture was stirred atambient temperature for 16 hours, diluted with ethyl acetate (300 mL),washed with 1M aqueous hydrochloric acid, brine, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The residue wasre-crystallized from ethyl acetate/hexanes mixture (1:2) to afford thetitle compound as a colorless solid (7.7 g, 56%): MS (ES−) m/z 294.1(M−1).

Step 2. Preparation of5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N-(cyclopropylsulfonyl)-2,4-difluorobenzamide and toreplace adamantan-1-ylmethanol with spiro[2.5]octan-6-ylmethanol, thetitle compound was obtained as a colorless solid (0.165 g, 28%): ¹H NMR(300 MHz, CDCl₃) δ8.72-8.59 (m, 1H), 8.16-8.07 (m, 1H), 6.76-6.65 (m,1H), 3.97-3.86 (m, 2H), 3.17-3.05 (m, 1H), 2.03-1.72 (m, 5H), 1.51-1.42(m, 2H), 1.36-1.11 (m, 4H), 1.00-0.90 (m, 2H), 0.38-0.14 (m, 4H); MS(ES+) m/z 416.2, 418.2 (M+1).

Example 210 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide

Following the procedure as described in Example 49 and making variationsas required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide,the title compound was obtained as a colorless solid (0.024 g, 18%): ¹HNMR (300 MHz, CDCl₃) δ8.76-8.62 (m, 1H), 7.63-7.54 (m, 1H), 6.63-6.53(m, 1H), 3.96-3.78 (m, 2H), 3.20-3.02 (m, 1H), 2.12-1.72 (m, 6H),1.50-1.41 (m, 2H), 1.40-1.22 (m, 2H), 1.20-1.10 (m, 2H), 1.02-0.88 (m,4H), 0.72-0.61 (m, 2H), 0.38-0.15 (m, 4H); MS (ES+) m/z 422.2 (M+1).

Example 211 Synthesis of5-cyclopropyl-4-((4,4-difluorocyclohexyl)methoxy)-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide

Step 1. Preparation of-chloro-4-((4,4,-difluorocyclohexyl)methoxy)-2-fluorobenzoic acid

Following the procedure as described in Example 158 step 1 and makingvariations as required to replace(1-(trifluoromethyl)cyclohexyl)methanol with(4,4-difluorocyclohexyl)methanol, the title compound was obtained as apale yellow oil (5.28 g, 99%) containing o-substituted regioisomer,which was used for next step without further purification: MS (ES−) m/z321.1, 323.1 (M−1).

Step 2. Preparation of tert-butyl 5-cyclopropyl-4-((4,4-difluoro-cyclohexyl)methoxy)-2-fluorobenzoate

To a solution of5-chloro-4-((4,4-difluorocyclohexyl)methoxy)-2-fluorobenzoic acid

(5.28 g, 16.36 mmol) and N,N-dimethylpyridin-4-amine (0.092 g, 0.82mmol) in tert-butanol (35 mL) was added di-tert-butyldicarbonate (7.50g, 34.36 mmol). The reaction mixture was heated at 50° C. for 16 hours.Additional di-tert-butyldicarbonate (3.57 g, 16.36 mmol) was added. Thereaction mixture was stirred at 50° C. for 6 hours and then concentratedin vacuo. The residue was purified by column chromatography eluting witha gradient of ethyl acetate in hexanes (0-10%) to afford a pale yellowoil (5.9 g) that was dissolved in the mixture of toluene (62 mL) andwater (3 mL). Cyclopropylboronic acid (2.01 g, 23.36 mmol), potassiumphosphate (14.88 g, 70.11 mmol), tricyclohexylphosphinetetrafluoroborate (0.574 g, 1.56 mmol), and palladium acetate (0.175 g,0.78 mmol) were added under a nitrogen atmosphere and the reactionmixture was stirred at 100° C. for 16 hours. The mixture was cooled toambient temperature, water (60 mL) was added and the mixture extractedwith ethyl acetate. The combined organics were washed with brine, driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo.Purification of the residue by column chromatography eluting with agradient of ethyl acetate in hexanes (0-10%) afforded the title compound(5.37 g, 86%) as a pale yellow oil: MS (ES−) m/z 383.0 (M−1).

Step 3. Preparation of5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acid

Following the procedure as described in Example 158 step 4, and makingvariations as required to replace tert-butyl5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)benzoatewith tert-butyl5-cyclopropyl-4-((4,4-difluorocyclohexyl)methoxy)-2-fluorobenzoate, thetitle compound was obtained as a colorless solid (2.29 g, 50%): MS (ES+)m/z 329.1 (M+1).

Step 4. Preparation of5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoicacid with5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acidand to replace methanesulfonamide with 2-methoxyethanesulfonamide, thetitle compound was obtained (0.072 g, 26%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ8.70-8.58 (m, 1H), 7.63-7.53 (m, 1H), 6.63-6.51 (m,1H), 3.93-3.83 (m, 4H), 3.83-3.75 (m, 2H), 3.31 (s, 3H), 2.27-2.09 (m,2H), 2.08-1.66 (m, 6H), 1.61-1.42 (m, 2H), 0.99-0.88 (m, 2H), 0.71-0.60(m, 2H); MS (ES+) m/z 450.0 (M+1).

Example 212 Synthesis of5-cyclopropyl-4-((4,4-difluorocyclohexyl)methoxy)-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoicacid with5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acidand to replace methanesulfonamide with 3-fluoroazetidine-1-sulfonamide,the title compound was obtained (0.12 g, 43%) as a colorless solid: ¹HNMR (300 MHz, CDCl₃) δ8.77-8.64 (m, 1H), 7.64-7.55 (m, 1H), 6.62-6.53(m, 1H), 5.43-5.13 (m, 1H), 4.57-4.31 (m, 4H), 3.94-3.86 (m, 2H),2.27-2.11 (m, 2H), 2.09-1.68 (m, 6H), 1.61-1.43 (m, 2H), 0.99-0.90 (m,2H), 0.71-0.63 (m, 2H); MS (ES+) m/z 465.0 (M+1).

Example 213 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzamide

Following the procedure as described in preparation of Example 158 step5, and making variations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoicacid with5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acidand to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained (0.14 g, 47%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ8.72-8.57 (m, 1H), 7.66-7.54 (m, 1H), 6.64-6.50 (m,1H), 4.32-4.19 (m, 4H), 3.96-3.83 (m, 2H), 2.35-2.09 (m, 4H), 2.09-1.68(m, 6H), 1.62-1.41 (m, 2H), 1.04-0.87 (m, 2H), 0.76-0.62 (m, 2H); MS(ES+) m/z 447.0 (M+1).

Example 214 Synthesis of5-cyclopropyl-4-((4,4-difluorocyclohexyl)methoxy)-2-fluoro-N-(N-methylsulfamoyl)benzamide

Following the procedure as described in Example 158 step 5 and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoicacid with5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acidand to replace methanesulfonamide with (methylsulfamoyl)amine, the titlecompound was obtained (0.08 g, 29%) as a colorless solid: ¹H NMR (300MHz, CDCl₃) δ8.77-8.64 (m, 1H), 7.62-7.51 (m, 1H), 6.65-6.52 (m, 1H),5.30-5.18 (m, 1H), 3.95-3.85 (m, 2H), 2.83-2.72 (m, 3H), 2.28-1.66 (m,8H), 1.57-1.42 (m, 2H), 1.01-0.90 (m, 2H), 0.71-0.60 (m, 2H); MS (ES+)m/z 421.1 (M+1).

Example 215 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoicacid with5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acidand to replace methanesulfonamide with cyclopropanesulfonamide, thetitle compound was obtained (0.144 g, 46%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ8.74-8.63 (m, 1H), 7.64-7.56 (m, 1H), 6.61-6.52 (m,1H), 3.93-3.84 (m, 2H), 3.16-3.04 (m, 1H), 2.26-2.08 (m, 2H), 2.08-1.66(m, 6H), 1.60-1.42 (m, 4H), 1.20-1.10 (m, 2H), 0.99-0.89 (m, 2H),0.70-0.61 (m, 2H); MS (ES+) m/z 432.0 (M+1).

Example 216 Synthesis of5-chloro-2-fluoro-4-((2-fluoroadamantan-2-yl)methoxy)-N-(methylsulfonyl)benzamide

Step 1. Preparation of (2-fluoroadamantan-2-yl)methanol

To a stirred solution of methyl 2-fluoroadamantane-2-carboxylate (0.90g, 4.20 mmol) (Zhurnal Organicheskoi Khimii, 1981, 17, 1642) intetrahydrofuran (40 mL) was added methanol (0.24 mL, 5.90 mmol),followed by the addition of lithium borohydride solution (2.0 M intetrahydrofuran, 5.3 mL, 10.60 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 15 minutes, at ambient temperature for 30 minutesand then at reflux for 1 hour. The reaction mixture was cooled toambient temperature and poured in small portions into a cooled to 0° C.saturated ammonium chloride solution (25 mL) with stirring. The mixturewas stirred at ambient temperature for 1 hour and extracted with ethylacetate (3×70 mL). The combined organic layers were washed with brine(100 mL), dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo to afford (2-fluoroadamantan-2-yl)methanol (0.69g, 88%) as colorless solid: MS (ES+) m/z 223.2 (M+39).

Step 2. Preparation of5-chloro-2-fluoro-4-((2-fluoroadamantan-2-yl)methoxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace adamantan-1-ylmethanol with(2-fluoroadamantan-2-yl)methanol, the title compound was obtained as acolorless solid (0.23 g, 10%): ¹H NMR (300 MHz, CDCl₃) δ 8.74-8.63 (m,1H), 8.16-8.07 (m, 1H), 6.83-6.73 (m, 1H), 4.36 (d, J=24.60 Hz, 2H),3.43 (s, 3H), 2.36-2.15 (m, 4H), 1.98-1.84 (m, 4H), 1.82-1.62 (m, 6H);MS (ES−) m/z 432.1 (M−1).

Example 217 Synthesis of5-cyclopropyl-2-fluoro-4-((2-fluoroadamantan-2-yl)methoxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 49 and making variationsas required to replace4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamidewith5-chloro-2-fluoro-4-((2-fluoroadamantan-2-yl)methoxy)-N-(methylsulfonyl)benzamide,the title compound was obtained as a colorless solid (0.24 g, 74%): ¹HNMR (300 MHz, CDCl₃) δ8.77-8.65 (m, 1H), 7.63-7.56 (m, 1H), 6.68-6.58(m, 1H), 4.30 (d, J=24.85 Hz, 2H), 3.42 (s, 3H), 2.34-2.16 (m, 4H),2.14-2.01 (m, 1H), 1.97-1.85 (m, 4H), 1.84-1.72 (m, 4H), 1.72-1.62 (m,2H), 1.00-0.90 (m, 2H), 0.70-0.61 (m, 2H); MS (ES−) m/z 438.1 (M−1).

Example 218 Synthesis oftrans-N-(azetidin-1-ylsulfonyl)-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzamide

Step 1. Preparation of5-chloro-4-((5-chloroadamantan-2-yl)oxy)-2-fluorobenzoic acid

To a solution of 5-chloroadamantan-2-ol (2.00 g, 10.70 mmol) inanhydrous dimethylsulfoxide (50 ml) was added potassium tert-butoxide(3.01 g, 26.80 mmol) and the reaction mixture was stirred at ambienttemperature for 30 minutes. 5-chloro-2,4-difluorobenzoic acid (2.06 g,10.70 mmol) was added to the reaction mixture, stirring was continuedfor 2 hours. The reaction mixture was acidified to pH=1 with 5% aqueoushydrochloric acid solution and diluted with water (100 mL), the whiteprecipitate was filtered, washed with water and dried to afforded thetitle compound as colorless solid (3.30 g, 86%), containingo-substituted regioisomer, which was used for next step without furtherpurification: MS (ES+) m/z 359.2, 361.2 (M+1), MS (ES−) m/z 357.1, 359.1(M−1).

Step 2. Preparation of trans-tert-butyl5-chloro-4-((5-chloroadamantan-2-yl)oxy)-2-fluorobenzoate

And cis-tert-butyl5-chloro-4-((5-chloroadamantan-2-yl)oxy)-2-fluorobenzoate

To a solution of5-chloro-4-((5-chloroadamantan-2-yl)oxy)-2-fluorobenzoic acid (3.0 g,8.35 mmol) and N,N-dimethylpyridin-4-amine (0.10 g, 0.82 mmol) intert-butanol (25 mL) was added di-tert-butyldicarbonate (3.65 g, 16.70mmol). The reaction mixture was heated at 50° C. for 16 hours, andconcentrated in vacuo. The crude product was purified by columnchromatography (0-15% ethyl acetate in hexanes) to afford twodiastereomers. The first fraction as trans-tert-butyl5-chloro-4-((5-chloroadamantan-2-yl)oxy)-2-fluorobenzoate (1.48 g, 43%):¹H NMR (300 MHz, DMSO-d₆) δ 7.81 (d, J=7.7 Hz, 1H), 7.34 (d, J=13.0 Hz,1H), 4.89 (t, J=3.3 Hz, 1H), 2.33-2.13 (m, 9H), 1.99-1.94 (m, 2H),1.52-1.48 (m, 11H); MS (ES+) m/z 359.1, 361.1 (M−55). The secondfraction as cis-tert-butyl5-chloro-4-((5-chloroadamantan-2-yl)oxy)-2-fluorobenzoate (0.50 g, 14%):¹H NMR (300 MHz, DMSO-d₆) δ 7.83 (d, J=7.7 Hz, 1H), 7.33 (d, J=13.0 Hz,1H), 4.75 (t, J=3.0 Hz, 1H), 2.40-2.32 (m, 4H), 2.09 (br s, 3H),1.96-1.92 (m, 2H), 1.79-1.73 (m, 4H), 1.92 (s, 9H);

Step 3. Preparation of trans-tert-butyl4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoate

To a solution of trans-tert-butyl5-chloro-4-((5-chloroadamantan-2-yl)oxy)-2-fluorobenzoate (0.94 g, 2.19mmol), cyclopropylboronic acid (0.28 g, 3.29 mmol), potassium phosphate(2.09 g, 9.85 mmol) and tricyclohexylphosphine tetrafluoroborate (0.08g, 0.22 mmol) in toluene (20 mL) and water (1 mL) under a nitrogenatmosphere was added palladium acetate (0.03 g, 0.11 mmol). The reactionmixture was heated at 100° C. for 18 hours and then cooled to ambienttemperature. Water (20 mL) was added and the mixture extracted withethyl acetate, the combined organics were washed with brine; dried overanhydrous sodium sulfate and concentrated in vacuo. Purification of theresidue by column chromatography (5% ethyl acetate in hexanes) affordedthe title compound (0.70 g, 76%): MS (ES+) m/z 421.2, 423.2 (M+1).

Step 4. Preparation oftrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acid

To a solution of trans-tert-butyl4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoate (0.70 g,1.67 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (5ml). The reaction mixture was stirred at ambient temperature for 2 hoursand then concentrated in vacuo. The residue was purified by columnchromatography (5% to 60% ethyl acetate contains 0.2% acetic acid inhexanes) afforded the title compound as colorless solid (0.17 g, 29%):¹H NMR (300 MHz, DMSO-d₆) δ 12.83 (s, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.02(d, J=12.4 Hz, 1H), 4.79 (t, J=2.8 Hz, 1H), 2.35-2.27 (m, 4H), 2.17-1.97(m, 8H), 1.53-1.49 (m, 2H), 0.93-0.87 (m, 2H), 0.63-0.56 (m, 2H); MS(ES+) m/z 365.1, 367.1 (M+1); MS (ES−) m/z 363.2, 365.2 (M−1).

Preparation ofcis-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acid

To a solution of cis-tert-butyl5-chloro-4-((5-chloroadamantan-2-yl)oxy)-2-fluorobenzoate (3.94 g, 9.49mmol), cyclopropylboronic acid (1.22 g, 14.2 mmol), potassium phosphate(3.02 g, 14.2 mmol) and tricyclohexylphosphine tetrafluoroborate (0.50g, 0.95 mmol) in toluene (100 mL) and water (5 mL) under a nitrogenatmosphere was added palladium acetate (0.21 g, 0.95 mmol). The reactionmixture was heated to 100° C. for 18 hours and then cooled to ambienttemperature. Water (20 mL) was added and the mixture extracted withethyl acetate, the combined organics were washed with brine; dried overanhydrous sodium sulfate and concentrated in vacuo., the crude productcis-tert-butyl4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoate was indichloromethane (30 mL) and added trifluoroacetic acid (10 ml). Thereaction mixture was stirred at ambient temperature for 2 hours and thenconcentrated in vacuo. The residue was purified by column chromatography(5% to 60% gradient ethyl acetate contains 0.2% acetic acid in hexanes)to afford the title compound as off-white solid (2.48 g, 72%): ¹H NMR(300 MHz, DMSO-d₆) δ 12.78 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.02 (d,J=13.3 Hz, 1H), 4.65 (t, J=2.8 Hz, 1H), 2.43-2.27 (m, 4H), 2.17-1.93 (m,7H), 1.78 (s, 3H), 0.93-0.87 (m, 2H), 0.63-0.56 (m, 2H); MS (ES+) m/z365.1, 367.1 (M+1);

Step 5. Synthesis oftrans-N-(azetidin-1-ylsulfonyl)-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzamide

To a mixture oftrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acid(0.17 g, 0.47 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.21g, 1.07 mmol) and 4-dimethylaminopyridine (0.13 g, 1.07 mmol) inanhydrous dichloromethane (10 mL) was added azetidine-1-sulfonamide(0.15 g, 1.07 mmol) at ambient temperature. The resulting mixture wasstirred at ambient temperature for 16 h. The mixture was quenched withhydrochloride acid (1N, 30 mL) followed by extraction with ethyl acetate(100 mL). The organic layer was washed with water (30 mL), dried overanhydrous sodium sulfate, and filtered. The filtrate was concentrated invacuo, the crude product was purified by silica gel columnchromatography using 10-60% ethyl acetate (containing 2% acetic acid) inhexanes as an elute to afford the title compound as colorless solid(0.10 g, 42%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.59 (s, 1H), 7.18-7.07 (m,2H), 4.82-4.80 (m, 1H), 4.04 (t, J=7.7 Hz, 4H), 2.36-2.28 (m, 4H),2.19-1.97 (m, 10H), 1.52 (d, J=12.5 Hz, 2H), 0.94-0.87 (m, 2H),0.71-0.66 (m, 2H); MS (ES+) m/z 483.1, 485.1 (M+1); MS (ES−) m/z 481.2,483.2 (M−1).

Example 219 Synthesis oftrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluoro-N-(morpholinosulfonyl)benzamide

Following the procedure as described in Example 218 step 5 and makingvariations as required to replace azetidine-1-sulfonamide withmorpholine-4-sulfonamide, the title compound was obtained as colorlesssolid (0.04 g, 18%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.70 (s, 1H),7.14-7.06 (m, 2H), 4.82-4.80 (m, 1H), 3.65-3.62 (m, 4H), 3.27-3.24 (m,4H), 2.36-2.27 (m, 4H), 2.18-1.85 (m, 8H), 1.53-1.49 (m, 2H), 0.93-0.87(m, 2H), 0.71-0.65 (m, 2H); MS (ES+) m/z 513.0, 515.0 (M+1); MS (ES−)m/z 511.1, 513.1 (M−1).

Example 220 Synthesis ofcis-N-(azetidin-1-ylsulfonyl)-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 218 step 5 and makingvariations as required to replacetrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acidwith cis-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as colorless solid (0.16 g, 48%):¹H NMR (300 MHz, DMSO-d₆) δ 11.60 (s, 1H), 7.19 (d, J=8.3 Hz, 1H), 7.09(d, J=13.1 Hz, 1H), 4.68 (t, J=2.6 Hz, 1H), 4.04 (t, J=7.70 Hz, 4H),2.43-2.35 (m, 4H), 2.21-2.04 (m, 6H), 1.98-1.94 (m, 2H), 1.79 (br,s,4H), 0.95-0.89 (m, 2H), 0.73-0.68 (m, 2H); MS (ES+) m/z 483.1, 485.1(M+1); MS (ES−) m/z 481.2, 483.2 (M−1).

Example 221 Synthesis ofcis-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 218 step 5 and makingvariations as required to replacetrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acidwith cis-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoicacid and to replace azetidine-1-sulfonamide withcyclopropanesulfonamide, the title compound was obtained as colorlesssolid (0.17 g, 53%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.81 (s, 1H), 7.18 (d,J=8.4 Hz, 1H), 7.09 (d, J=13.2 Hz, 1H), 4.67 (t, J=2.6 Hz, 1H),3.12-3.03 (m, 1H), 2.43-2.35 (m, 4H), 2.10-2.02 (m, 4H), 1.95 (d, J=11.7Hz, 2H), 1.79 (br,s, 4H), 1.13-1.09 (m, 4H), 0.95-0.89 (m, 2H),0.72-0.67 (m, 2H); MS (ES+) m/z 468.1, 470.1 (M+1); MS (ES−) m/z 466.2,468.2 (M−1).

Example 222 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclobutyl)methoxy)benzamide

Step 1. Preparation of5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)methoxy)benzoic acid

Following the procedure as described in Example 218 step 1 and makingvariations as required to replace 5-chloroadamantan-2-ol with(1-(trifluoromethyl)cyclobutyl)methanol, the title compound was obtainedas beige color solid (2.10 g, 99%): MS (ES−) m/z 325.1, 327.1 (M−1);

Step 2. Preparation of tert-butyl5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclobutyl)methoxy)benzoate

Following the procedure as described in Example 218 step 2 and makingvariations as required to replace5-chloro-4-((5-chloroadamantan-2-yl)oxy)-2-fluorobenzoic acid with5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)methoxy)benzoicacid, the title compound was obtained as clear liquid (2.41 g, 99%): MS(ES+) m/z 327.1, 329.1 (M−55).

Step 3. Preparation of5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclobutyl)methoxy)benzoicacid

To a solution of tert-butyl5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)-methoxy)benzoate(2.11 g, 5.5 mmol), cyclopropylboronic acid (0.94 g, 11.0 mmol),potassium phosphate (5.25 g, 24.8 mmol) and tricyclohexylphosphinetetrafluoroborate (0.4 g, 1.10 mmol) in toluene (60 mL) and water (3 mL)under a nitrogen atmosphere was added palladium acetate (0.25 g, 1.10mmol). The reaction mixture was heated to 110° C. for 18 hours and thencooled to ambient temperature. Water (20 mL) was added and the mixtureextracted with ethyl acetate, the combined organics were washed withbrine; dried over anhydrous sodium sulfate and concentrated in vacuo.,the crude product tert-butyl5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)-methoxy)benzoatewas dissolved in dichloromethane (30 mL) and added trifluoroacetic acid(10 ml). The reaction mixture was stirred at ambient temperature for 2hours and then concentrated in vacuo. The residue was purified by columnchromatography (5% to 60% ethyl acetate contains 0.2% acetic acid inhexanes) afforded the title compound was obtained as colorless solid(0.50, 27%): MS (ES+) m/z 333.1 (M+1); MS (ES−) m/z 331.2 (M−1).

Step 4. Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclobutyl)methoxy)benzamide

Following the procedure as described in Example 218 step 5 and makingvariations as required to replacetrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)methoxy)benzoicacid, the title compound was obtained as colorless solid (0.11 g, 55%):¹H NMR (300 MHz, DMSO-d₆) δ 11.67 (s, 1H), 7.17 (d, J=8.2 Hz, 1H), 7.11(d, J=12.8 Hz, 1H), 4.34 (s, 2H), 4.05 (t, J=7.7 Hz, 4H), 2.38-2.27 (m,2H), 2.22-2.11 (m, 5H), 2.01-1.93 (m, 2H), 0.91-0.84 (m, 2H), 0.71-0.65(m, 2H); MS (ES+) m/z 451.1 (M+1); MS (ES−) m/z 449.2 (M−1).

Example 223 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclobutyl)methoxy)benzamide

Following the procedure as described in Example 218 step 5 and makingvariations as required to replacetrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)methoxy)benzoicacid and to replace azetidine-1-sulfonamide withcyclopropanesulfonamide, the title compound was obtained as colorlesssolid (0.09 g, 47%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.88 (s, 1H),7.17-7.09 (m, 2H), 4.34 (s, 2H), 3.12-3.04 (m, 1H), 2.38-2.27 (m, 2H),2.19-2.09 (m, 3H), 2.03-1.94 (m, 2H), 1.14-1.10 (m, 4H), 0.90-0.84 (m,2H), 0.70-0.64 (m, 2H); MS (ES+) m/z 436.1 (M+1); MS (ES−) m/z 434.2(M−1).

Example 224 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclobutyl)methoxy)benzamide

Following the procedure as described in Example 218 step 5 and makingvariations as required to replacetrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)methoxy)benzoicacid, the title compound was obtained as colorless solid (0.08 g, 55%):¹H NMR (300 MHz, DMSO-d₆) δ 11.88 (s, 1H), 7.81 (d, J=7.4 Hz, 1H), 7.40(d, J=12.2 Hz, 1H), 4.42 (s, 2H), 4.06 (t, J=7.7 Hz, 4H), 2.37-2.27 (m,2H), 2.23-2.09 (m, 5H), 2.02-1.92 (m, 1H); MS (ES+) m/z 445.0, 447.0(M+1); MS (ES−) m/z 443.1, 445.1 (M−1).

Example 225 Synthesis of5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(trifluoromethyl)-cyclobutyl)methoxy)benzamide

Following the procedure as described in Example 218 step 5 and makingvariations as required to replacetrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)methoxy)benzoicacid and to replace azetidine-1-sulfonamide withcyclopropanesulfonamide, the title compound was obtained as colorlesssolid (0.04 g, 47%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (s, 1H), 7.78 (d,J=7.5 Hz, 1H), 7.39 (d, J=12.4 Hz, 1H), 4.41 (s, 2H), 3.12-3.03 (m, 1H),2.37-2.27 (m, 2H), 2.18-2.09 (m, 3H), 2.01-1.92 (m, 1H), 1.15-1.11 (m,4H); MS (ES+) m/z 430.0, 432.0 (M+1); MS (ES−) m/z 428.1, 430.1 (M−1).

Example 226 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)-methoxy)-2-fluorobenzamide

Step 1. Preparation of tert-butyl5-chloro-4-((4,4-difluoroadamantan-1-yl)-methoxy)-2-fluorobenzoate

To a solution of (4,4-difluoroadamantan-1-yl)methanol (1.00 g, 4.90mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (1.84 g, 7.40 mmol)in anhydrous dimethylsulfoxide (20 mL) was added cesium carbonate (3.22g, 9.90 mmol). The mixture was stirred at 70° C. for 16 hours. Themixture was then cooled to ambient temperature, and mixed with water (50mL). The white solid was filtered and washed with hexanes and dried byair give the title compound as colorless solid (1.70 g, 80%): MS (ES+)m/z 431.1, 433.1 (M+1); 375.0, 377.0 (M−55).

Step 2. Preparation of tert-butyl5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)-methoxy)-2-fluorobenzoate

To a solution of tert-butyl5-chloro-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluorobenzoate (1.50g, 3.48 mmol), cyclopropylboronic acid (0.45 g, 5.22 mmol), potassiumphosphate (3.33 g, 15.7 mmol) and tricyclohexylphosphinetetrafluoroborate (0.13 g, 0.35 mmol) in toluene (60 mL) and water (3mL) under a nitrogen atmosphere was added palladium acetate (0.08 g,0.35 mmol). The reaction mixture was heated to 100° C. for 18 hours andthen cooled to ambient temperature. Water (20 mL) was added and themixture was filtered through a pad of diatomaceous earth and the solidwas washed with ethyl acetate (150 mL). The organics were washed withbrine; dried over anhydrous sodium sulfate and concentrated in vacuo.Purification of the residue by crystallization (ethyl acetate andhexanes) afforded the title compound as colorless solid (1.00 g, 66%):¹H NMR (300 MHz, CDCl₃) δ 7.42 (d, J=8.4 Hz, 1H), 6.47 (d, J=12.6 Hz,1H), 3.57 (s, 2H), 2.29 (br s, 2H), 2.02-1.95 (m, 6H), 1.75-1.68 (m,6H), 1.57 (s, 9H), 0.93-0.87 (m, 2H), 0.65-0.60 (m, 2H); MS (ES+) m/z459.2 (M+23).

Step 3. Preparation of5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluorobenzoicacid

To a solution of tert-butyl5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)-methoxy)-2-fluorobenzoate(1.0 g, 2.29 mmol) in dichloromethane (20 mL) was added trifluoroaceticacid (15 ml). The reaction mixture was stirred at ambient temperaturefor 2 hours and then concentrated in vacuo. The residue was trituratedin mixture of dichloromethane and hexanes afforded the title compound ascolorless solid (0.82 g, 94%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.83 (s,1H), 7.34 (d, J=8.5 Hz, 1H), 6.88 (d, J=13.1 Hz, 1H), 3.57 (s, 2H), 2.24(br s, 2H), 2.04-1.95 (m, 2H), 1.87-1.68 (m, 10H), 0.93-0.87 (m, 2H),0.65-0.56 (m, 2H); MS (ES+) m/z 381.1 (M+1); MS (ES−) m/z 379.2 (M−1).

Step 4. Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluorobenzamide

To a mixture of5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)-methoxy)-2-fluorobenzoicacid (0.25 g, 0.66 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(0.29 g, 1.51 mmol) and 4-dimethylaminopyridine (0.19 g, 1.51 mmol) inanhydrous dichloromethane (10 mL) was added azetidine-1-sulfonamide(0.13 g, 0.99 mmol) at ambient temperature. The resulting mixture wasstirred at ambient temperature for 16 hours. The mixture was quenchedwith 1N hydrochloride acid (30 mL), followed by extraction with ethylacetate (100 mL). The organic layer was washed with water (30 mL), driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated in vacuo, the crude product was crystallized from ethylacetate and hexanes and recrystallized from acetonitrile and water toafford the title compound as colorless solid (0.24 g, 73%): ¹H NMR (300MHz, DMSO-d₆) δ 11.61 (s, 1H), 7.17 (d, J=8.3 Hz, 1H), 6.94 (d, J=12.9Hz, 1H), 4.05 (t, J=7.7 Hz, 4H), 3.72 (s, 2H), 2.25-1.98 (m, 6H),1.88-1.69 (m, 10H), 0.94-0.87 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z499.1 (M+1); MS (ES−) m/z 497.2 (M−1).

Example 227 Synthesis of5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide

Following the procedure as described in Example 226 step 4 and makingvariations as required to replace azetidine-1-sulfonamide with2-methoxyethanesulfonamide, the title compound was obtained as colorlesssolid (0.17 g, 70%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.89 (s, 1H), 7.13 (d,J=8.3 Hz, 1H), 6.93 (d, J=12.9 Hz, 1H), 3.72-3.71 (m, 6H), 3.21 (s, 3H),2.25 (br s, 2H), 2.05-1.96 (m, 2H), 1.87-1.68 (m, 10H), 0.94-0.87 (m,2H), 0.69-0.63 (m, 2H); MS (ES+) m/z 502.1 (M+1); MS (ES−) m/z 500.2(M−1).

Example 228 Synthesis of5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 226 step 4, and makingvariations as required to replace azetidine-1-sulfonamide with3-fluoroazetidine-1-sulfonamide, the title compound was obtained ascolorless solid (0.24 g, 70%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.81 (s,1H), 7.17 (d, J=8.3 Hz, 1H), 6.95 (d, J=12.9 Hz, 1H), 5.48-5.42 (m,0.5H), 5.29-5.23 (m, 0.5H), 4.43-4.30 (m, 2H), 4.25-4.12 (m, 2H), 3.72(s, 2H), 2.25 (bs, 2H), 2.05-1.96 (m, 2H), 1.87-1.68 (m, 10H), 0.94-0.87(m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 517.1 (M+1); MS (ES−) m/z 515.2(M−1).

Example 229 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4,4-difluoroadamantan-1-yl)-methoxy)-2-fluorobenzamide

Following the procedure as described in Example 226 Step 4 and makingvariations as required to replace azetidine-1-sulfonamide withcyclopropanesulfonamide, the title compound was obtained as colorlesssolid (0.27 g, 85%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.83 (s, 1H), 7.15 (d,J=8.3 Hz, 1H), 6.94 (d, J=12.9 Hz, 1H), 3.72 (s, 2H), 3.49 (br s, 1H),2.25 (br s, 2H), 2.05-1.96 (m, 2H), 1.87-1.68 (m, 10H), 1.13-1.09 (m,4H), 0.94-0.87 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 484.1 (M+1); MS(ES−) m/z 482.2 (M−1).

Example 230 Synthesis of4-(adamantan-1-ylmethoxy)-N-((3-cyanoazetidin-1-yl)sulfonyl)-5-cyclopropyl-2-fluorobenzamide

To a mixture of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoicacid (0.20 g, 0.60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(0.26 g, 1.38 mmol) and 4-dimethylaminopyridine (0.17 g, 1.38 mmol) inanhydrous dichloromethane (10 mL) was added3-cyanoazetidine-1-sulfonamide (0.22 g, 1.38 mmol) at ambienttemperature. The resulting mixture was stirred at ambient temperaturefor 16 hours. The mixture was quenched with 1 M aqueous hydrochlorideacid (30 mL) followed by extraction with ethyl acetate (100 mL). Theorganic layer was washed with water (30 mL), dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated in vacuo, theresidue was purified by silica gel column chromatography using 10-60%ethyl acetate (containing 2% acetic acid) in hexanes as an elute toafford the title compound as colorless solid (0.23 g, 79%): ¹H NMR (300MHz, DMSO-d₆) δ 11.88 (s, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.95 (d, J=13.0Hz, 1H), 4.35-4.22 (m, 4H), 3.84-3.74 (m, 1H), 3.65 (s, 2H), 2.09-1.99(m, 4H), 1.75-1.67 (m, 12H), 0.95-0.87 (m, 2H), 0.70-0.65 (m, 2H); MS(ES+) m/z 488.2 (M+1); MS (ES−) m/z 486.3 (M−1).

Example 231 Synthesis ofN-(2-oxa-7-azaspiro[3.5]nonan-7-ylsulfonyl)-4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 230 and makingvariations as required to replace 3-cyanoazetidine-1-sulfonamide with2-oxa-7-azaspiro[3.5]nonane-7-sulfonamide, the title compound wasobtained as colorless solid (0.01 g, 14%): ¹H NMR (300 MHz, DMSO-d₆) δ11.60 (s, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.89 (d, J=12.9 Hz, 1H), 4.29 (s,4H), 3.63 (s, 2H), 3.21-3.17 (m, 4H), 2.05-1.99 (m, 4H), 1.85-1.82 (m,4H), 1.75-1.66 (m, 12H), 0.93-0.87 (m, 2H), 0.67-0.62 (m, 2H); MS (ES+)m/z 533.1 (M+1); MS (ES−) m/z 531.2 (M−1).

Example 232 Synthesis ofN-(2-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)-4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 230 and makingvariations as required to replace 3-cyanoazetidine-1-sulfonamide with2-oxa-6-azaspiro[3.3]heptane-6- sulfonamide, the title compound wasobtained as colorless solid (0.11 g, 17%): ¹H NMR (300 MHz, DMSO-d₆) δ11.68 (s, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.93 (d, J=12.9 Hz, 1H), 4.63 (s,4H), 4.24 (s, 4H), 3.64 (s, 2H), 2.05-1.99 (m, 4H), 1.75-1.66 (m, 12H),0.94-0.88 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 505.1 (M+1); MS (ES−)m/z 503.2 (M−1).

Example 233 Synthesis of3-((4-((azetidin-1-ylsulfonyl)carbamoyl)-2-cyclopropyl-5-fluorophenoxy)-methyl)adamantan-1-yl2,2,2-trifluoroacetate

Following the procedure as described in Example 230 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-2-fluoro-4-((3-(2,2,2-trifluoroacetoxy)adamantan-1-yl)methoxy)benzoicacid and to replace 3-cyanoazetidine-1-sulfonamide withazetidine-1-sulfonamide, the title compound was obtained as colorlesssolid (0.22 g, 47%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.62 (s, 1H), 7.17 (d,J=8.3 Hz, 1H), 6.95 (d, J=12.9 Hz, 1H), 4.05 (t, J=7.7 Hz, 4H), 3.79 (s,2H), 2.32 (br s, 2H), 2.19-2.14 (m, 8H), 2.06-2.00 (m, 1H), 1.70-1.59(m, 6H), 0.95-0.88 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 575.1 (M+1);MS (ES−) m/z 573.1 (M−1).

Example 234 Synthesis ofN-(1-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)-4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 230 and makingvariations as required to replace 3-cyanoazetidine-1-sulfonamide with1-oxa-6-azaspiro[3.3]heptane-6-sulfonamide, the title compound wasobtained as colorless solid (0.20 g, 61%): ¹H NMR (300 MHz, DMSO-d₆) δ11.69 (s, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.93 (d, J=13.0 Hz, 1H), 4.37 (t,J=7.5 Hz, 2H), 4.23 (dd, J=10.2 Hz, 22.3 Hz, 4H), 3.64 (s, 2H), 2.80 (t,J=7.5 Hz, 2H), 2.08-1.99 (m, 4H), 1.85-1.82 (m, 4H), 1.75-1.66 (m, 12H),0.94-0.88 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 505.1 (M+1); MS (ES−)m/z 503.2 (M−1).

Example 235 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((3-hydroxyadamantan-1-yl)methoxy)benzamide

Following the procedure as described in Example 230 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-2-fluoro-4-((3-hydroxyadamantan-1-yl)methoxy)benzoic acidand to replace 3-cyanoazetidine-1-sulfonamide withazetidine-1-sulfonamide, the title compound was obtained as colorlesssolid (0.08 g, 65%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.60 (s, 1H), 7.15 (d,J=8.3 Hz, 1H), 6.94 (d, J=12.9 Hz, 1H), 4.47 (s, 1H), 4.04 (t, J=7.7 Hz,4H), 3.70 (s, 2H), 2.21-2.11 (m, 4H), 2.07-1.98 (m, 1H), 1.58-1.53 (m,12H), 0.95-0.88 (m, 2H), 0.71-0.66 (m, 2H); MS (ES+) m/z 479.1 (M+1); MS(ES−) m/z 477.2 (M−1).

Example 236 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((4-hydroxypiperidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 230 and makingvariations as required to replace 3-cyanoazetidine-1-sulfonamide with4-hydroxypiperidine-1-sulfonamide, the title compound was obtained ascolorless solid (0.01 g, 14%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.57 (s,1H), 7.09 (d, J=8.3 Hz, 1H), 6.91 (d, J=12.9 Hz, 1H), 4.76 (d, J=3.9 Hz,1H), 3.63-3.47 (m, 5H), 3.12-3.04 (m, 2H), 2.07-1.99 (m, 4H), 1.79-1.66(m, 14H), 1.48-1.37 (m, 2H), 0.93-0.87 (m, 2H), 0.68-0.63 (m, 2H); MS(ES+) m/z 507.2 (M+1); MS (ES−) m/z 505.3 (M−1).

Example 237 Synthesis of(R)-4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-methoxypyrrolidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 230 and makingvariations as required to replace 3-cyanoazetidine-1-sulfonamide with(R)-3-methoxypyrrolidine-1-sulfonamide, the title compound was obtainedas colorless solid (0.34 g, 87%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.55 (s,1H), 7.09 (d, J=8.3 Hz, 1H), 6.91 (d, J=12.9 Hz, 1H), 4.00-3.95 (m, 1H),3.63 (s, 2H), 3.56-3.40 (m, 4H), 3.19 (s, 3H), 2.05-1.87 (m, 6H),1.75-1.66 (m, 12H), 0.93-0.85 (m, 2H), 0.68-0.63 (m, 2H); MS (ES+) m/z507.2 (M+1); MS (ES−) m/z 505.3 (M−1).

Example 238 Synthesis of(S)-4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-methoxypyrrolidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 230 and makingvariations as required to replace 3-cyanoazetidine-1-sulfonamide with(S)-3-methoxypyrrolidine-1- sulfonamide, the title compound was obtainedas colorless solid (0.20 g, 98%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.55 (s,1H), 7.09 (d, J=8.3 Hz, 1H), 6.91 (d, J=12.9 Hz, 1H), 3.98-3.95 (m, 1H),3.63 (s, 2H), 3.56-3.40 (m, 4H), 3.19 (s, 3H), 2.07-1.87 (m, 6H),1.75-1.66 (m, 12H), 0.93-0.87 (m, 2H), 0.68-0.63 (m, 2H); MS (ES+) m/z507.2 (M+1); MS (ES−) m/z 505.3 (M−1).

Example 239 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-vinylbenzamide

Following the procedure as described in Example 230 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-2-fluoro-5-vinylbenzoic acid and3-cyanoazetidine-1-sulfonamide with azetidine-1-sulfonamide, the titlecompound was obtained as colorless solid (0.13 g, 36%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.75 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.04 (d, J=12.9 Hz,1H), 6.91 (dd, J=11.3 Hz, 17.8 Hz, 1H), 5.93 (dd, J=1.0 Hz, 17.8 Hz,1H), 5.37 (dd, J=1.0 Hz, 11.3 Hz, 1H), 4.06 (t, J=7.7 Hz, 4H), 3.67 (s,2H), 2.23-2.12 (m, 2H), 2.00-1.99 (m, 3H), 1.75-1.64 (m, 12H); MS (ES+)m/z 449.1 (M+1); MS (ES−) m/z 447.3 (M−1).

Example 240 Synthesis ofcis-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((4-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 49 and making variationsas required to replace4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamidewithcis-5-chloro-2-fluoro-N-(methylsulfonyl)-4-((4-(trifluoromethyl)cyclohexyl)methoxy)benzamide,the title compound was obtained as colorless solid (0.12 g, 24%): ¹H NMR(300 MHz, DMSO-d₆) δ 11.89 (s, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.04 (d,J=13.1 Hz, 1H), 4.06 (d, J=7.1 Hz, 2H), 3.34 (s, 3H), 2.36-2.28 (m, 1H),2.13-1.97 (m, 2H), 1.74-1.56 (m, 8H), 0.91-0.85 (m, 2H), 0.70-0.65 (m,2H); MS (ES+) m/z 438.1 (M+1); MS (ES−) m/z 436.2 (M−1).

Example 241/242 Synthesis oftrans-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((4-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

And synthesis oftrans-2-fluoro-N-(methylsulfonyl)-4-((4-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 49 and making variationsas required to replace4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamidewithtrans-5-chloro-2-fluoro-N-(methylsulfonyl)-4-((4-(trifluoromethyl)cyclohexyl)methoxy)benzamide,the title compound was obtained as colorless solid (0.06 g, 47%): ¹H NMR(300 MHz, DMSO-d₆) δ 11.89 (s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.95 (d,J=13.0 Hz, 1H), 3.92 (d, J=6.1 Hz, 2H), 3.33 (s, 3H), 2.30-2.20 (m, 1H),2.08-1.81 (m, 6H), 1.38-1.12 (m, 4H), 0.93-0.87 (m, 2H), 0.70-0.65 (m,2H); MS (ES+) m/z 438.1 (M+1); MS (ES−) m/z 436.2 (M−1).

trans-2-fluoro-N-(methylsulfonyl)-4-((4-(trifluoromethyl)cyclohexyl)methoxy)benzamidewas also obtained as colorless solid (0.03 g, 22%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.95 (s, 1H), 7.63 (t, J=8.7 Hz, 1H), 6.97-6.85 (m, 2H),3.89 (d, J=6.4 Hz, 2H), 3.32 (s, 3H), 2.30-2.20 (m, 1H), 1.93-189 (m,4H), 1.80-173. (m, 1H), 1.35-1.06 (m, 4H); MS (ES+) m/z 398.1 (M+1); MS(ES−) m/z 396.2 (M−1).

Example 243 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((trans-5-methoxyadamantan-2-yl)oxy)benzamide

Step 1. Preparation of5-chloro-2-fluoro-4-((trans-5-methoxyadamantan-2-yl)oxy)benzoic acid

And 5-chloro-2-fluoro-4-((cis-5-methoxyadamantan-2-yl)oxy)benzoic acid

To a solution of 5-methoxyadamantan-2-ol (6.50 g, 35.67 mmol) inanhydrous dimethylsulfoxide (60 ml) was added potassium tert-butoxide(10.00 g, 89.11 mmol) and the reaction mixture was stirred at ambienttemperature for 30 minutes. 5-chloro-2,4-difluorobenzoic acid (6.86 g,35.62 mmol) was added to the reaction mixture, stirring was continuedfor 2 hours. The reaction mixture was acidified to pH=1 with 5% aqueoushydrochloric acid solution and diluted with water (100 mL); extractedwith ethyl acetate (100 mL×3). The combined organic extracts was washedwith water and dried and concentrated in vacuo. The residue was purifiedby column chromatography (10-50% ethyl acetate in hexanes) to afford twodiastereomers. The first fraction as5-chloro-2-fluoro-4-((trans-5-methoxyadamantan-2-yl)oxy)benzoic acid(1.20 g, 9%): MS (ES−) m/z 353.2, 351.2 (M−1). The second fraction as5-chloro-2-fluoro-4-((cis-5-methoxyadamantan-2-yl)oxy)benzoic acid (0.8g, 6%): MS (ES−) m/z 53.2, 351.2 (M−1).

Step 2. Preparation ofN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((trans-5-methoxyadamantan-2-yl)oxy)benzamide

To a stirred solution of5-chloro-2-fluoro-4-((trans-5-methoxyadamantan-2-yl)- oxy)benzoic acid(1.20 g, 3.38 mmol) in dichloromethane (100 mL) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.97 g,5.05 mmol), and 4-dimethylaminopyridine (0.94 g, 7.69 mmol). Thereaction stirred at ambient temperature for 10 minutes,azetidine-1-sulfonamide (0.69 g, 5.07 mmol) was added and the stirringcontinued at ambient temperature for 17 hours. 5% aqueous hydrochloricacid solution (10 mL) were added and diluted with ethyl acetate (300mL), washed with water and brine; dried over anhydrous sodium sulfateand concentrated in vacuo. Purification of the residue by columnchromatography (30% ethyl acetate in hexanes) afforded the titlecompound (1.08 g, 67%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.59 (d, J=15.3 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 6.68 (d, J=13.8 Hz,1H), 4.42-4.34 (m, 1H), 4.23 (t, J=7.5 Hz, 4H), 3.24 (s, 3H), 2.43 (brs, 2H), 2.32-2.17 (m, 5H), 1.85-1.62 (m, 6H), 1.57-1.50 (m, 2H); MS(ES+) m/z 473.1, 475.1 (M+1); MS (ES−) m/z 471.2, 473.2 (M−1).

Example 244 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((trans-5-methoxyadamantan-2-yl)oxy)benzamide

Following the procedure as described in Example 165 and makingvariations as required to replaceN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoro-methyl)cyclopentyl)-methoxy)benzamide withN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((trans-5-methoxyadamantan-2-yl)oxy)benzamide,the title compound was obtained (0.31 g, 64%) as a colorless solid: ¹HNMR (300 MHz, CDCl₃) δ 8.63 (d, J=16.2 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H),6.54 (d, J=14.7 Hz, 1H), 4.37-4.32 (m, 1H), 4.22 (t, J=7.8 Hz, 4H), 3.22(s, 3H), 2.44 (br s, 2H), 2.29-2.03 (m, 6H), 1.85-1.64 (m, 6H),1.59-1.52 (m, 2H), 0.96-0.88 (m, 2H), 0.68-0.62 (m, 2H); MS (ES+) m/z479.2 (M+1). MS (ES−) m/z 477.2 (M−1).

Example 245 SynthesisN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((cis-5-methoxyadamantan-2-yl)oxy)benzamide

Following the procedure as described in Example 243 step 2, and makingvariations as required to replace5-chloro-2-fluoro-4-((trans-5-methoxyadamantan-2-yl)oxy)benzoic acidwith 5-chloro-2-fluoro-4-((cis-5-methoxyadamantan-2-yl)oxy)benzoic acid,the title compound was obtained (0.27 g, 50%) as a colorless solid: ¹HNMR (300 MHz, CDCl₃) δ 8.61 (d, J=15.3 Hz, 1H), 8.12 (d, J=8.1 Hz, 1H),6.67 (d, J=13.8 Hz, 1H), 4.53-4.46 (m, 1H), 4.23 (t, J=7.8 Hz, 4H), 3.24(s, 3H), 2.38-2.07 (m, 7H), 1.88-1.74 (m, 6H), 1.49-1.40 (m, 2H); MS(ES+) m/z 475.1, 473.1 (M+1); MS (ES−) m/z 473.2, 471.2 (M−1).

Example 246 Synthesis of5-chloro-2-fluoro-4-((cis-5-methoxyadamantan-2-yl)oxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 243 step 2 and makingvariations as required to replace5-chloro-2-fluoro-4-((trans-5-methoxyadamantan-2-yl)oxy)benzoic acidwith 5-chloro-2-fluoro-4-((cis-5-methoxyadamantan-2-yl)oxy)benzoic acidand to replace azetidine-1-sulfonamide with methanesulfonamide, thetitle compound was obtained (0.14 g, 38%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ 8.66 (d, J=15.3 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 6.66(d, J=14.1 Hz, 1H), 4.48-4.52 (m, 1H), 3.40 (s, 3H), 3.24 (s, 3H),2.40-2.32 (m, 2H), 2.25-2.08 (m, 3H), 1.92-1.78 (m, 6H), 1.49-1.40 (m,2H); MS (ES+) m/z 434.0, 432.0 (M+1); MS (ES−) m/z 432.1, 430.1 (M−1).

Example 247 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((trans-4-methylcyclohexyl)-methoxy)benzamide

Step 1. Preparation of tert-butyl5-chloro-2-fluoro-4-((trans-4-methylcyclohexyl)-methoxy)benzoate

To a solution of trans-(4-methylcyclohexyl)methanol (3.00 g, 23.4 mmol)and tert-butyl 5-chloro-2,4-difluorobenzoate (6.43 g, 25.90 mmol) inanhydrous dimethylsulfoxide (40 mL) was added cesium carbonate (16.11 g,49.44 mmol). The mixture was heated at 70° C. for 96 hours, and thencooled to ambient temperature; diluted with water (300 mL) and extractedwith ethyl acetate (4×100 mL). The combined organic layers were washedwith water (100 mL) and brine (100 mL); dried over anhydrous sodiumsulfate; filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (0% to 10% ethyl acetate in hexanes gradient) togive the title compound (6.48 g 78%): ¹H NMR (300 MHz, CDCl₃) δ 7.87 (d,J=7.7 Hz, 1H), 6.61 (d, J=12.3 Hz, 1H), 3.82 (d, J=6.2 Hz, 2H),1.91-1.73 (m, 8H), 1.56 (s, 9H), 1.17-0.96 (m, 5H).

Step 2. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((trans-4-methyl-cyclohexyl)-methoxy)benzoate

To a solution of tert-butyl5-chloro-2-fluoro-4-((trans-4-methylcyclohexyl)-methoxy)-benzoate (6.48g, 18.16 mmol) in toluene-water (40 mL, v/v 20:1) was addedcyclopropylboronic acid (2.34 g, 27.26 mmol) and tribasic potassiumphosphate (17.37, 81.84 mmol). The reaction mixture was sparged withargon for 10 minutes and then charged with tricyclohexylphosphinetetrafluoroborate (1.35 g, 3.67 mmol) and palladium acetate (0.41 g,1.82 mmol). The mixture was heated at 110° C. for 72 hours, then cooledto ambient temperature; filtered through a pad of diatomaceous earth andwashed with ethyl acetate. The filtrate was concentrated in vacuo, andthe residue was purified by column chromatography (0% to 10% ethylacetate) to give the title compound (5.95 g, 90%): ¹H NMR (300 MHz,CDCl₃) δ 7.37 (d, J=8.4 Hz, 1H), 6.50 (d, J=12.8 Hz, 1H), 3.78 (d, J=6.1Hz, 2H), 1.91-1.70 (m, 8H), 1.56 (s, 9H), 1.41-129 (m, 2H), 1.14-0.95(m, 6H), 0.65-0.60 (m, 2H).

Step 3. Preparation of5-cyclopropyl-2-fluoro-4-((trans-4-methylcyclohexyl)-methoxy)benzoicacid

To a solution of tert-butyl5-cyclopropyl-2-fluoro-4-((trans-4-methyl-cyclohexyl)methoxy)benzoate(5.95 g, 16.41 mmol) in anhydrous dichloromethane (28 mL) was addedtrifluoroacetic acid (14 mL). The mixture was stirred for 1 hour atambient temperature, and then concentrated in vacuo. The solid wastriturated with methanol to give the title compound (2.42 g, 48%):): ¹HNMR (300 MHz, CDCl₃) δ 12.8 (br s, 1H), 7.30 (d, J=8.5 Hz, 1H), 6.88 (d,J=13.1 Hz, 1H), 3.89 (d, J=6.1 Hz, 2H), 2.05-1.96 (m, 1H), 1.85-1.68 (m,5H), 1.39-1.25 (m, 1H), 1.17-0.86 (m, 9H), 0.61-0.56 (m, 2H).

Step 4. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((trans-4-methylcyclohexyl)methoxy)benzamide

To a mixture of5-cyclopropyl-2-fluoro-4-((trans-4-methylcyclohexyl)-methoxy)benzoicacid (0.255 g, 0.83 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.242 g, 1.26 mmol) and 4-dimethylaminopyridine (0.242 g,1.98 mmol) in anhydrous dichloromethane (22 mL) was addedazetidine-1-sulfonamide (0.173 g, 1.27 mmol). The reaction mixture wasstirred at ambient temperature for 16 hours. The mixture was poured into5% aqueous hydrochloric acid (50 mL) and the layers were separated. Theaqueous layer was extracted with ethyl acetate (4×50 mL). The combinedorganic layers were washed with water (50 mL) and brine (50 mL); driedover anhydrous sodium sulfate; filtered and concentrated in vacuo. Theresidue was purified by column chromatography (0% to 40% ethyl acetatein hexanes) to afford the title compound (0.114 g, 33%) as a colorlesssolid: ¹H NMR (300 MHz, CDCl₃) δ 8.66 (d, J=16.7 Hz, 1H), 7.59 (d, J=9.1Hz, 1H), 6.57 (d, J=14.5 Hz, 1H), 4.25 (t, J=7.7 Hz, 4H), 3.83 (d, J=6.1Hz, 2H), 2.27 (q, J=7.7 Hz, 1H), 2.11-2.02 (m, 1H), 1.92-1.75 (m, 5H),1.41-1.29 (m, 1H), 1.25-0.90 (m, 10H), 0.70-0.64 (m, 2H); MS (ES−) m/z423.26 (M−1).

Example 248 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((trans-4-methylcyclohexyl)methoxy)benzamide

Following the procedure as described in Example 247 step 4 and makingvariations as required to replace azetidine-1-sulfonamide withcyclopropanesulfonamide, the title compound was obtained as a colorlesssolid (0.254 g, 83%): ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J=16.3 Hz, 1H),7.56 (d, J=9.1 Hz, 1H), 6.55 (d, J=14.5 Hz, 1H), 3.81 (d, J=6.1 Hz, 2H),3.12-3.04 (m, 1H), 2.08-1.99 (m, 1H), 1.89-1.73 (m, 5H), 1.46-0.83 (m,14H), 0.67-0.61 (m, 2H); MS (ES−) m/z 408.2 (M−1).

Example 249 Synthesis of5-cyclopropyl-2-fluoro-4-((trans-4-methylcyclohexyl)methoxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 247 step 4 and makingvariations as required to replace azetidine-1-sulfonamide withmethanesulfonamide, the title compound was obtained (0.188 g, 69%) as acolorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.71 (d, J=16.2 Hz, 1H), 7.56(d, J=9.1 Hz, 1H), 6.57 (d, J=14.6 Hz, 1H), 3.81 (d, J=6.1 Hz, 2H), 3.41(s, 3H), 2.10-2.00 (m, 1H), 1.91-1.75 (m, 5H), 1.44-1.28 (m, 1H),1.20-0.90 (m, 9H), 0.68-0.63 (m, 2H); MS (ES−) m/z 382.2 (M−1)

Example 250 Synthesis ofcis-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 218 step 5 and makingvariations as required to replacetrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acidwith cis-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoicacid and to replace azetidine-1-sulfonamide with methanesulfonamide, thetitle compound was obtained (0.18 g, 57%) as a colorless solid: ¹H NMR(300 MHz, DMSO-d₆) δ 11.88 (s, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.08 (d,J=13.2 Hz, 1H), 4.67 (t, J=3.0 Hz, 1H), 3.34 (s, 3H), 2.43-2.34 (m, 4H),2.10-2.02 (m, 4H), 1.97-1.93 (m, 2H), 1.79 (s, 4H), 0.95-0.89 (m, 2H),0.72-0.67 (m, 2H); MS (ES+) m/z 444.1, 442.1, (M+1); MS (ES−) m/z 442.2,440.2 (M−1).

Example 251 Synthesis ofcis-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 218 step 5, and makingvariations as required to replacetrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acidwith cis-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoicacid and to replace azetidine-1-sulfonamide with3-fluoroazetidine-1-sulfonamide, the title compound was obtained (0.23g, 65%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.80 (s, 1H),7.20 (d, J=8.3 Hz, 1H), 7.10 (d, J=13.1 Hz, 1H), 5.48-5.23 (m, 1H), 4.68(t, J=2.8 Hz, 1H), 4.43-4.31 (m, 2H), 4.25-4.12 (m, 2H), 2.43-2.35 (m,4H), 2.11-2.02 (m, 4H), 1.95 (d, J=11.6 Hz, 2H), 1.79 (br s, 4H),0.96-0.89 (m, 2H), 0.72-0.67 (m, 2H); MS (ES+) m/z 503.1, 501.1 (M+1);MS (ES−) m/z 501.1, 499.1 (M−1).

Example 252 Synthesis oftrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 218 step 5, and makingvariations as required to replace azetidine-1-sulfonamide with3-fluoroazetidine-1-sulfonamide, the title compound was obtained (0.03g, 69%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.80 (s, 1H),7.16 (d, J=8.3 Hz, 1H), 7.10 (d, J=13.1 Hz, 1H), 5.48-5.42 (m, 0.5H),5.29-5.23 (m, 0.5H), 4.82 (t, J=2.7 Hz, 1H), 4.42-4.30 (m, 2H),4.24-4.11 (m, 2H), 2.36-2.28 (m, 4H), 2.19-1.97 (m, 8H), 1.52 (d, J=12.5Hz, 2H), 0.94-0.88 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 503.1,501.1, (M+1); MS (ES−) m/z 501.1, 499.1 (M−1).

Example 253 Synthesis ofcis-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((4-(trifluoromethyl)cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 218 step 5, and makingvariations as required to replacetrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acidwithcis-5-cyclopropyl-2-fluoro-4-((4-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid, the title compound was obtained (0.10 g, 66%) as a colorlesssolid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.61 (s, 1H), 7.14 (d, J=8.3 Hz,1H), 7.05 (d, J=13.0 Hz, 1H), 4.07-4.02 (m, 6H), 2.39-2.27 (m, 1H),2.21-2.11 (m, 3H), 2.06-1.97 (m, 1H), 1.74-1.56 (m, 8H), 0.91-0.85 (m,2H), 0.71-0.65 (m, 2H); MS (ES+) m/z 479.1 (M+1); MS (ES−) m/z 477.2(M−1).

Example 254 Synthesis ofcis-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((4-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 218 step 5, and makingvariations as required to replacetrans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acidwithcis-5-cyclopropyl-2-fluoro-4-((4-(trifluoromethyl)cyclohexyl)-methoxy)benzoicacid and to replace azetidine-1-sulfonamide withcyclopropanesulfonamide, the title compound was obtained as colorlesssolid (0.11 g, 79%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.82 (s, 1H), 7.13 (d,J=8.3 Hz, 1H), 7.04 (d, J=13.1 Hz, 1H), 4.06 (d, J=7.1 Hz, 2H),3.11-3.03 (m, 1H), 2.42-2.26 (m, 1H), 2.14 (brs, 1H), 2.06-1.97 (m, 1H),1.74-1.56 (m, 8H), 1.13-1.09 (m, 4H), 0.91-0.85 (m, 2H), 0.69-0.64 (m,2H); MS (ES+) m/z 464.1 (M+1); MS (ES−) m/z 462.2 (M−1).

Example 255 Synthesis ofcis-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-methyl-4-(trifluoromethyl)cyclohexyl)methoxy)benzamide

Step 1. Preparation of methyl1-methyl-4-(trifluoromethyl)cyclohexanecarboxylate

To a solution of diisopropylamine (22.0 mL, 124.0 mmol) intetrahydrofuran (60 mL) was added n-BuLi (2.0 M solution in hexane, 59.0mL, 95.0 mmol) at 0° C. and the reaction mixture was allowed to stir atsame temperature for 20 minutes before cooled to −78° C. Methyl4-(trifluoromethyl)cyclohexanecarboxylate (10.0 g, 48.0 mmol) intetrahydrofuran (60 mL) was added dropwise at −78° C. The reactionmixture was stirred at same temperature for 2 hours and then neat methyliodide (4.5 mL, 72.0 mmol) was added dropwise. After stirring at −78° C.for 1 hour, the reaction mixture was warmed to ambient temperature andstirred for 16 hours, before quenched with 25% aqueous ammonium chloridesolution (100 mL) at 0° C. and extracted with ethyl acetate. The organiclayer was washed with brine; dried over anhydrous sodium sulfate andconcentrated in vacuo to afford the title compound (11.2 g, 99%) as abrown colored oil: ¹H NMR (300 MHz, CDCl₃) δ 3.70 (s, 3H), 2.32-2.28 (m,2H), 2.01-1.80 (m, 3H), 1.42-1.08 (m, 7H).

Step 2. Preparation of (1-methyl-4-(trifluoromethyl)cyclohexyl)methanol

To a solution of 1-methyl-4-(trifluoromethyl)cyclohexanecarboxylate(11.0 g, 49.00 mmol) in tetrahydrafuran (600 mL) was slowly addedlithium borohydride solution (4.0 M in tetrahydrofuran, 37.0 mL, 147.00mmol) and methanol (6.0 mL, 147.00 mmol) at 0° C. After stirring at 0°C. for 15 minutes, the reaction mixture was stirred at ambienttemperature for 16 hours. The reaction mixture was cooled to 0° C. andquenched with 25% aqueous ammonium chloride solution (100 mL), andextracted with ethyl acetate. The combined organic layers were washedwith brine; dried over anhydrous magnesium sulfate; filtered andconcentrated in vacuo. Purification of the residue by columnchromatography (0 to 5% gradient ethyl acetate in hexanes) afforded thetitle compound (6.80 g, 72%) as a colorless oil): ¹H NMR (300 MHz,CDCl₃) δ 3.51 (s, 2H), 2.02-1.91 (m, 1H), 1.75-1.72 (m, 4H), 1.49-1.35(m, 3H), 1.19-1.09 (m, 2H), 0.94 (s, 3H).

Step 3. Preparation of cis-tert-butyl5-chloro-2-fluoro-4-((1-methyl-4-(trifluoromethyl)cyclohexyl)-methoxy)benzoate

Following the procedure as described in Example 226 step 1, and makingvariations as required to replace (4,4-difluoroadamantan-1-yl)methanolwith (1-methyl-4-(trifluoromethyl)cyclohexyl)- methanol, the titlecompound was obtained (6.20 g, 95%) as colorless oil: ¹H NMR (300 MHz,CDCl₃) δ 7.88 (d, J=7.7 Hz, 1H), 6.65 (d, J=12.0 Hz, 1H), 3.85 (s, 2H),1.96-1.93 (m, 2H), 1.85-1.79 (m, 2H), 1.58 (s, 9H), 1.53-1.39 (m, 3H),1.34-1.23 (m, 2H), 1.11 (s, 3H),

Step 4. Preparation of cis-tert-butyl5-chloro-2-fluoro-4-((1-methyl-4-(trifluoromethyl)cyclohexyl)methoxy)benzoate

Following the procedure as described in Example 226 step 2, and makingvariations as required to replace tert-butyl5-chloro-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluorobenzoate withcis-tert-butyl5-chloro-2-fluoro-4-((1-methyl-4-(trifluoromethyl)cyclohexyl)methoxy)benzoate,the title compound was obtained (1.66 g, 96%) as a pale yellow oil: ¹HNMR (300 MHz, CDCl₃) δ 7.42 (d, J=8.4 Hz, 1H), 6.53 (d, J=12.6 Hz, 1H),3.81 (s, 2H), 2.00-1.95 (m, 3H), 1.84-1.79 (m, 2H), 1.57 (s, 9H),1.55-1.41 (m, 2H), 1.33-1.22 (m, 2H), 1.11 (s, 3H), 0.91-0.85 (m, 2H),0.64-0.59 (m, 2H).

Step 5. Preparation ofcis-5-cyclopropyl-2-fluoro-4-((1-methyl-4-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid

Following the procedure as described in Example 226 step 3, and makingvariations as required to replace tert-butyl5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)-methoxy)-2-fluorobenzoatewith cis-tert-butyl5-chloro-2-fluoro-4-((1-methyl-4-(trifluoromethyl)cyclohexyl)-methoxy)benzoate,the title compound was obtained as light yellow gummy solid (1.30 g,81%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.84 (s, 1H), 7.33 (d, J=8.5 Hz, 1H),7.02 (d, J=13.2 Hz, 1H), 3.92 (s, 2H), 2.26-2.20 (m, 1H), 2.04-1.95 (m,1H), 1.87-1.83 (m, 2H), 1.72-1.67 (m, 2H), 1.54-1.41 (m, 2H), 1.34-1.23(m, 2H), 1.05 (s, 3H), 0.91-0.85 (m, 2H), 0.60-0.55 (m, 2H); MS (ES−)m/z 373.2 (M−1).

Step 6. Preparation ofcis-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-methyl-4-(trifluoromethyl)cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 226 step 4, and makingvariations as required to replace5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluorobenzoicwithcis-5-cyclopropyl-2-fluoro-4-((1-methyl-4-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid, the title compound was obtained as (0.13 g, 64%) a colorlesssolid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.60 (s, 1H), 7.16 (d, J=8.3 Hz,1H), 7.09 (d, J=13.0 Hz, 1H), 4.04 (t, J=7.7 Hz, 4H), 3.93 (s, 2H),2.31-2.11 (m, 3H), 2.06-1.97 (m, 1H), 1.88-1.83 (m, 2H), 1.73-1.68 (m,2H), 1.54-1.41 (m, 2H), 1.35-1.25 (m, 2H), 1.06 (s, 3H), 0.92-0.86 (m,2H), 0.70-0.64 (m, 2H); MS (ES+) m/z 493.2 (M+1); MS (ES−) m/z 491.3(M−1).

Example 256 Synthesis ofcis-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-methyl-4-(trifluoromethyl)cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 226 step 4, and makingvariations as required to replace5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluorobenzoicwithcis-5-cyclopropyl-2-fluoro-4-((1-methyl-4-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid and to replace azetidine-1-sulfonamide withcyclopropanesulfonamide, the title compound was obtained (0.11 g, 61%)as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.82 (s, 1H), 7.15(d, J=8.3 Hz, 1H), 7.09 (d, J=13.1 Hz, 1H), 3.93 (s, 2H), 3.12-3.03 (m,1H), 2.30-2.20 (m, 1H), 2.05-1.96 (m, 1H), 1.87-1.83 (m, 2H), 1.73-1.68(m, 2H), 1.54-1.41 (m, 2H), 1.34-1.24 (m, 2H), 1.13-1.08 (m, 4H), 1.05(s, 3H), 0.92-0.85 (m, 2H), 0.69-0.63 (m, 2H); MS (ES+) m/z 478.1 (M+1);MS (ES−) m/z 476.2 (M−1).

Example 257 Synthesis ofcis-5-cyclopropyl-2-fluoro-4-((1-methyl-4-(trifluoromethyl)-cyclohexyl)methoxy)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 226 step 4, and makingvariations as required to replace5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluorobenzoicwithcis-5-cyclopropyl-2-fluoro-4-((1-methyl-4-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid, and to replace azetidine-1-sulfonamide with methanesulfonamide,the title compound was obtained (0.11 g, 58%) as a colorless solid: ¹HNMR (300 MHz, DMSO-d₆) δ 11.89 (s, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.08 (d,J=13.1 Hz, 1H), 3.93 (s, 2H), 3.33 (s, 3H), 2.30-2.20 (m, 1H), 2.06-1.96(m, 1H), 1.87-1.83 (m, 2H), 1.73-1.68 (m, 2H), 1.54-1.41 (m, 2H),1.34-1.24 (m, 2H), 1.05 (s, 3H), 0.92-0.85 (m, 2H), 0.69-0.64 (m, 2H);MS (ES+) m/z 452.1 (M+1); MS (ES−) m/z 450.2 (M−1).

Example 258 Synthesis oftrans-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((4-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 226 step 4, and makingvariations as required to replace5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluorobenzoicwithtrans-5-cyclopropyl-2-fluoro-4-((4-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid, the title compound was obtained (0.15 g, 78%) as a colorlesssolid: 11H NMR (300 MHz, DMSO-d₆) δ11.61 (s, 1H), 7.13 (d, J=8.3 Hz,1H), 6.96 (d, J=13.0 Hz, 1H), 4.04 (t, J=7.7 Hz, 4H), 3.92 (d, J=6.1 Hz,2H), 2.30-1.78 (m, 8H), 1.38-1.12 (m, 5H), 0.93-0.87 (m, 2H), 0.70-0.65(m, 2H); MS (ES+) m/z 479.1 (M+1); MS (ES−) m/z 477.2 (M−1).

Example 259 Synthesis oftrans-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((4-(trifluoromethyl)-cyclohexyl)methoxy)benzamide

Following the procedure as described in Example 226 step 4, and makingvariations as required to replace5-cyclopropyl-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluorobenzoicwithtrans-5-cyclopropyl-2-fluoro-4-((4-(trifluoromethyl)cyclohexyl)-methoxy)benzoicacid and to replace azetidine-1-sulfonamide withcyclopropanesulfonamide, the title compound was obtained (0.15 g, 81%)as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.82 (s, 1H), 7.12(d, J=8.3 Hz, 1H), 6.96 (d, J=13.0 Hz, 1H), 3.92 (d, J=6.0 Hz, 2H),3.12-3.03 (m, 1H), 2.08-1.78 (m, 6H), 1.38-1.10 (m, 9H), 0.93-0.87 (m,2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 464.1 (M+1); MS (ES−) m/z 462.2(M−1).

Example 260 Synthesis of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(((2s,3aR,4S,7R,7aS)-octahydro-1H-4,7-methanoinden-2-yl)methoxy)benzamide

Following the procedure as described in Example 49 and making variationsas required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with5-chloro-2-fluoro-N-(methylsulfonyl)-4-(((2s,3aR,4S,7R,7aS)-octahydro-1H-4,7-methanoinden-2-yl)methoxy)benzamide,the title compound was obtained (0.06 g, 59%) as a colorless solid: ¹HNMR (300 MHz, DMSO-d₆) δ 11.88 (s, 1H), 7.15-7.12 (m, 1H), 6.96-6.90 (m,1H), 3.95-3.79 (m, 2H), 3.32 (s, 3H), 2.43-2.36 (m, 2H), 2.18-1.96 (m,4H), 1.70-1.23 (m, 9H), 1.06-0.99 (m, 1H), 0.90-0.87 (m, 2H), 0.70-0.66(m, 2H); MS (ES+) m/z 422.2 (M+1); MS (ES−) m/z 420.3 (M−1).

Example 261 Synthesis of5-chloro-N-(ethylsulfonyl)-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide

Step 1. Preparation of 5-chloro-N-(ethylsulfonyl)-2,4-difluorobenzamide

Following the procedure as described in preparation of Example 209 step1, and making variations as required to replace cyclopropanesulfonamidewith ethanesulfonamide, the title compound was obtained (3.8 g, 70%) asa colorless solid: MS (ES+) m/z 284.0, 286.0 (M+1).

Step 2. Synthesis of5-chloro-N-(ethylsulfonyl)-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide

Following the procedure as described in Example 8 and making variationsas required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamidewith 5-chloro-N-(ethylsulfonyl)-2,4-difluorobenzamide and to replaceadamantan-1-ylmethanol with spiro[2.5]octan-6-ylmethanol, the titlecompound was obtained as a colorless solid (0.378 g, 46%): ¹H NMR (300MHz, CDCl₃) δ8.59-8.47 (m, 1H), 8.13-8.05 (m, 1H), 6.75-6.66 (m, 1H),3.97-3.86 (m, 2H), 3.66-3.55 (m, 2H), 2.02-1.72 (m, 5H), 1.48-1.40 (m,3H), 1.35-1.22 (m, 2H), 1.01-0.89 (m, 2H), 0.37-0.15 (m, 4H); MS (ES+)m/z 404.1, 406.1 (M+1).

Example 262 Synthesis of5-cyclopropyl-N-(ethylsulfonyl)-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide

A mixture of5-cyclopropyl-N-(ethylsulfonyl)-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide(0.055 g, 0.14 mmol), cyclopropylboronic acid (0.036 g, 0.41 mmol), andpotassium phosphate (0.297 g, 1.40 mmol) in toluene (3 mL) and water(0.3 mL) was sparged with nitrogen for 10 minutes.Tricyclohexylphosphine tetrafluoroborate (0.031 g, 0.084 mmol) andpalladium acetate (0.0095 g, 0.042 mmol) were added and the reactionmixture was heated at 150° C. for 1 hour under microwave irradiation.The mixture was cooled to ambient temperature, diluted with ethylacetate (100 mL) and 1M aqueous hydrochloric acid (20 mL). Layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×50mL). The combined organic layer was washed with brine (100 mL), driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo.Purification of the residue by column chromatography with a gradient ofethyl acetate in hexanes (0-70%) afforded the title compound (0.036 g,63%) as colorless solid: (0.036 g, 63%): ¹H NMR (300 MHz, CDCl₃) δ?8.61-8.50 (m, 1H), 7.60-7.51 (m, 1H), 6.63-6.54 (m, 1H), 3.93-3.83 (m,2H), 3.67-3.51 (m, 2H), 2.14-1.98 (m, 1H), 1.99-1.72 (m, 5H), 1.50-1.40(m, 3H), 1.37-1.22 (m, 2H), 1.02-0.88 (m, 4H), 0.72-0.60 (m, 2H),0.38-0.15 (m, 4H); MS (ES+) m/z 410.2 (M+1).

Example 263 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzamide

Step 1. Preparation of tert-butyl5-chloro-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzoate

And tert-butyl5-chloro-2-fluoro-4-((cis-5-fluoroadamantan-2-yl)oxy)benzoate

Following the procedure as described in preparation of Example 178 step1, and making variations as required to replace(4,4-difluoro-1-methylcyclohexyl)methanol with 5-fluoroadamantan-2-ol(J. Am. Chem. Soc. 1986, 108, 1598), the crude product was purified bycolumn chromatography with a gradient of ethyl acetate in hexanes (0-5%)to afford two diastereomers. The first fraction, tert-butyl5-chloro-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzoate (1.44 g,19%) as colorless solid: ¹H NMR (300 MHz, CDCl₃) δ? 7.92-7.86 (m, 1H),6.67-6.58 (m, 1H), 4.55-4.45 (m, 1H), 2.41 (s, 2H), 2.28 (s, 1H),2.20-1.92 (m, 8H), 1.60-1.56 (m, 9H), 1.52-1.39 (m, 2H); MS (ES+) m/z399.1, 401.2 (M+1);

The second fraction, tert-butyl5-chloro-2-fluoro-4-((cis-5-fluoroadamantan-2-yl)oxy)benzoate (0.81 g,11%) as colorless solid: ¹H NMR (300 MHz, CDCl₃) δ? 7.93-7.86 (m, 1H),6.67-6.59 (m, 1H), 4.38-4.29 (m, 1H), 2.57-2.46 (m, 2H), 2.44-2.21 (m,3H), 1.96-1.87 (m, 2H), 1.87-1.62 (m, 6H), 1.60-1.56 (m, 9H); MS (ES+)m/z 399.2 (M+1).

Step 2. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzoate

Following the procedure as described in preparation of Example 158 step3, and making variations as required to replace tert-butyl5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)-methoxy)benzoatewith tert-butyl5-chloro-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzoate, thetitle compound was obtained as colorless solid (1.43 g, 100%): MS (ES+)m/z 427.1 (M+23).

Step 3. Preparation of5-cyclopropyl-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzoic acid

Following the procedure as described in Example 158 step 4, and makingvariations as required to replace tert-butyl5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoatewith tert-butyl5-cyclopropyl-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzoate,the title compound was obtained as a colorless solid (1.01 g, 89%): MS(ES+) m/z 349.1 (M+1).

Step 4. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid with5-cyclopropyl-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzoic acidand to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained (0.149 g, 51%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ8.72-8.58 (m, 1H), 7.68-7.59 (m, 1H), 6.60-6.50 (m,1H), 4.56-4.46 (m, 1H), 4.33-4.19 (m, 4H), 2.51-2.39 (m, 2H), 2.35-2.20(m, 3H), 2.17-1.93 (m, 9H), 1.54-1.43 (m, 2H), 1.00-0.89 (m, 2H),0.75-0.61 (m, 2H); MS (ES+) m/z 467.1 (M+1).

Example 264 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoicacid with5-cyclopropyl-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzoic acidand to replace methanesulfonamide with cyclopropanesulfonamide, thetitle compound was obtained (0.149 g, 52%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ 8.75-8.60 (m, 1H), 7.68-7.58 (m, 1H), 6.60-6.47 (m,1H), 4.54-4.46 (m, 1H), 3.17-3.02 (m, 1H), 2.51-2.39 (m, 2H), 2.35-2.24(m, 1H), 2.17-1.91 (m, 9H), 1.63-1.41 (m, 4H), 1.21-1.07 (m, 2H),1.00-0.88 (m, 2H), 0.73-0.60 (m, 2H); MS (ES+) m/z 452.1 (M+1).

Example 265 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((cis-5-fluoroadamantan-2-yl)oxy)benzamide

Step 1. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((cis-5-fluoroadamantan-2-yl)oxy)benzoate

Following the procedure as described in preparation of Example 158 step3, and making variations as required to replace tert-butyl5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)benzoatewith tert-butyl5-chloro-2-fluoro-4-((cis-5-fluoroadamantan-2-yl)oxy)benzoate, the titlecompound was obtained as colorless solid (0.28 g, 34%): MS (ES+) m/z405.2 (M+1).

Step 2. Preparation of5-cyclopropyl-2-fluoro-4-((cis-5-fluoroadamantan-2-yl)oxy)benzoic acid

Following the procedure as described in Example 158 step 4, and makingvariations as required to replace tert-butyl5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoatewith tert-butyl5-cyclopropyl-2-fluoro-4-((cis-5-fluoroadamantan-2-yl)oxy)benzoate, thetitle compound was obtained as a colorless solid (0.200 g, 83%): MS(ES+) m/z 349.1 (M+1).

Step 3. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((cis-5-fluoroadamantan-2-yl)oxy)benzamide

Following the procedure as described in Example 158 step 5, and makingvariations as required to replace5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoicacid with5-cyclopropyl-2-fluoro-4-((trans-5-fluoroadamantan-2-yl)oxy)benzoic acidand to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained (0.137 g, 52%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ8.71-8.55 (m, 1H), 7.69-7.59 (m, 1H), 6.63-6.49 (m,1H), 4.40-4.31 (m, 1H), 4.32-4.18 (m, 4H), 2.62-2.48 (m, 2H), 2.39-2.19(m, 5H), 2.15-2.01 (m, 1H), 1.98-1.89 (m, 2H), 1.89-1.66 (m, 6H),1.04-0.90 (m, 2H), 0.72-0.61 (m, 2H); MS (ES+) m/z 467.1 (M+1).

Example 266 Synthesis of5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)-N-(methylsulfonyl)benzamide

Step 1. Preparation of tert-butyl5-chloro-2-fluoro-4-((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methoxy)benzoate

To a solution of (8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methanol (4.30g, 23 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (10.66 g, 30mmol) in anhydrous dimethylsulfoxide (37 mL) was added cesium carbonate(14.99 g, 46 mmol). The reaction mixture was heated to 70° C. andstirred for 4 days. At this point, HPLC and TLC analysis indicatedremaining starting material, but the reaction was not progressing anyfurther. The reaction mixture was cooled to ambient temperature,filtered through a pad of diatomaceous earth and rinsed with ethylacetate (100 mL). The filtrate was washed with 1N aqueous hydrochloricacid solution (100 mL). The organic layer was separated, washed withbrine (40 ml), dried over anhydrous sodium sulfate and concentrated invacuo. Purification of the residue by column chromatography (0% to 20%ethyl acetate in hexanes) afforded the title compound (5.13 g, 54%) as acolorless oil: MS (ES+) m/z 359.1 (M−55).

Step 2. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methoxy)benzoate

To a solution of tert-butyl5-chloro-2-fluoro-4-((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methoxy)benzoate(3.09 g, 7.45 mmol), cyclopropylboronic acid (0.96 g, 11.17 mmol),potassium phosphate (7.12 g, 33.53 mmol) and tricyclohexylphosphinetetrafluoroborate (0.28 g, 0.75 mmol) in toluene (50 mL) and water (2.5mL). The resulting suspension was sparged with Argon for 15 minutesbefore the addition of palladium acetate (0.083 g, 0.37 mmol). Thereaction mixture was heated at 100° C. for 18 hours and then cooled toambient temperature; filtered through a pad of diatomaceous earth andrinsed with ethyl acetate. The filtrate was diluted with additionalwater (20 mL). The organic layer was separated, washed with brine, driedover anhydrous sodium sulfate and concentrated in vacuo. The residue wasfiltered through a plug of silica gel (100% ethyl acetate) to afford thetitle compound (2.59 g, 83%) as a colorless oil: MS (ES+) m/z 365.2(M−55).

Step 3. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((1-methyl-4-oxocyclohexyl)methoxy)benzoate

To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methoxy)benzoate (2.59 g, 6.16 mmol) intetrahydrofuran (6 mL) and water (4.3 mL) was added trifluoroacetic acid(2.2 mL, 27.72 mmol). The reaction mixture was stirred at ambienttemperature for 18 hours. The reaction was quenched with 2 M aqueoussodium hydroxide solution (5 mL) before being diluted with saturatedaqueous sodium bicarbonate (20 mL) and ethyl acetate (50 mL). Theaqueous layer was separated and extracted with ethyl acetate (3×50 mL).The combined organics were dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. Purification of the residue by columnchromatography (0% to 15% ethyl acetate in hexanes) afforded the titlecompound (2.09 g, 90%) as a colorless oil: MS (ES+) m/z 321.2 (M−55).

Step 4. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((1-methyl-4-methylenecyclohexyl)methoxy)benzoate

To a cooled (−20° C.) suspension of methyltriphenylphosphonium bromide(1.44 g, 4.02 mmol) in tetrahydrofuran (12 mL) was added lithiumhexamethyldisilazide (1M solution in tetrahydrofuran, 4.0 mL, 4.00mmol). After 90 minutes, a solution of tert-butyl5-cyclopropyl-2-fluoro-4-((1-methyl-4-oxocyclohexyl)methoxy)benzoate(1.00 g, 2.68 mmol) in tetrahydrofuran (6 mL) was added. The reactionmixture was slowly warmed to ambient temperature and stirred for 12hours. The reaction was quenched with saturated aqueous ammoniumchloride solution (20 mL) and diluted with ethyl acetate (100 mL). Theaqueous layer was separated and extracted with ethyl acetate (3×30 mL).The combined organics were washed with brine, dried over anhydroussodium sulfate and concentrated in vacuo. Purification of the residue bycolumn chromatography (0% to 5% ethyl acetate in hexanes) afforded thetitle compound (0.83 g, 82%) as a colourless oil: MS (ES+) m/z 319.1(M−55).

Step 5. Preparation oftert-butyl-5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)benzoate

To a cooled (0° C.) solution of tert-butyl5-cyclopropyl-2-fluoro-4-((1-methyl-4-methylenecyclohexyl)methoxy)benzoate(0.30 g, 0.804 mmol) in 1,2-dichloroethane (2 mL), was addedchloroiodomethane (0.21 mL, 2.65 mmol), followed by diethylzinc (1Msolution in hexanes, 1.33 mL, 1.33 mmol). The reaction mixture wasstirred at 0° C. for 2 hours and then quenched with 1N aqueoushydrochloric acid solution. The aqueous layer was separated andextracted with dichloromethane (3×30 mL). The combined organics weredried over anhydrous sodium sulfate and concentrated in vacuo.Purification of the residue by column chromatography (0% to 5% ethylacetate in hexanes) afforded the title compound (0.29 g, 93%) as acolorless oil: MS (ES+) m/z 333.2 (M−55).

Step 6. Preparation of 5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)benzoic acid

To a cooled (0° C.) solution of tert-butyl5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)benzoate(0.277 g, 0.713 mmol) and anisole (0.11 mL, 1.07 mmol) indichloromethane (3 mL) was added trifluoroacetic acid (0.75 mL, 9.61mmol). The reaction mixture was stirred at 0° C. for 4 hours beforebeing quenched with water (5 mL). The reaction was diluted withdichloromethane (20 mL) and washed with water (4×10 mL) until the lastwash was neutral as monitored by pH paper. The organic layer was driedover anhydrous sodium sulfate and concentrated in vacuo to afford thetitle compound (0.213 g, 90%) as a white solid: MS (ES−) m/z 331.3(M−1).

Step 7. Preparation of 5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)-N-(methylsulfonyl)benzamide

To a stirred solution of5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)benzoicacid (0.085 g, 0.256 mmol) in dichloromethane (7 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.076 g,0.384 mmol) and 4-dimethylaminopyridine (0.072 g, 0.589 mmol). Thereaction mixture was stirred at ambient temperature for 10 minutes;methanesulfonamide (0.039 g, 0.41 mmol) was added and the stirringcontinued at ambient temperature for 17 hours. The reaction mixture wasconcentrated, diluted with ethyl acetate (20 mL) and washed with 5%aqueous hydrochloric acid solution (10 mL). The organic layer wasseparated and washed with water and brine, dried over anhydrous sodiumsulfate and concentrated in vacuo. Purification of the residue by columnchromatography (0% to 30% ethyl acetate in hexanes) afforded the titlecompound (0.058 g, 55%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.70(d, J=16.5 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 6.58 (d, J=14.6 Hz, 1H),3.74 (s, 2H), 3.40 (s, 3H), 2.09-1.95 (m, 1H), 1.69-1.42 (m, 6H),1.29-1.02 (m, 5H), 0.96-0.87 (m, 2H), 0.67-0.60 (m, 2H), 0.31-0.16 (m,4H); MS (ES−) m/z 408.3 (M−1).

Example 267 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)benzamide

Following the procedure as described in Example 266 step 7, and makingvariations as required to replace methanesulfonamide withazetidine-1-sulfonamide, the title compound was obtained (0.074 g, 39%)as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.65 (d, J=16.5 Hz, 1H),7.61 (d, J=9.1 Hz, 1H), 6.58 (d, J=14.5 Hz, 1H), 4.23 (t, J=7.7 Hz, 4H),3.74 (s, 2H), 2.32-2.18 (m, 2H), 2.08-1.94 (m, 1H), 1.67-1.40 (m, 6H),1.26-1.03 (m, 5H), 0.98-0.79 (m, 2H), 0.67-0.61 (m, 2H), 0.30-0.16 (m,4H); MS (ES−) m/z 449.3 (M−1).

Example 268 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)benzamide

Following the procedure as described in Example 266 step 7 and makingvariations as required to replace methanesulfonamide withcyclopropanesulfonamide, the title compound was obtained (0.046 g, 41%)as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.68 (d, J=16.3 Hz, 1H),7.60 (d, J=9.1 Hz, 1H), 6.57 (d, J=14.5 Hz, 1H), 3.74 (s, 2H), 3.14-3.04(m, 1H), 2.07-1.93 (m, 1H), 1.67-1.38 (m, 7H), 1.26-1.00 (m, 7H),0.96-0.77 (m, 3H), 0.67-0.60 (m, 2H), 0.30-0.16 (m, 4H); MS (ES−) m/z434.3 (M−1).

Example 269 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1,1-difluoro-6-methylspiro[2.5]octan-6-yl)methoxy)-2-fluorobenzamide

Step 1. Preparation of tert-butyl 5-cyclopropyl-4-((1,1-difluoro-6-methylspiro[2.5]octan-6-yl)methoxy)-2-fluorobenzoate

To a 10 mL microwave tube charged with tert-butyl5-cyclopropyl-2-fluoro-4-((1-methyl-4-methylenecyclohexyl)methoxy)benzoate(0.475 g, 1.27 mmol) and tetrahydrofuran (4 mL) was addedtrimethyl(trifluoromethyl)silane (0.375 mL, 2.54 mmol) and sodium iodide(0.42 g, 2.79 mmol). The reaction mixture was heated at 115° C. for 1hour. After cooling to ambient temperature, additionaltrimethyl(trifluoromethyl)silane (0.375 mL, 2.54 mmol) and sodium iodide(0.42 mg, 2.79 mmol) were added. The reaction was heated at 115° C. foranother 1 hour. After cooling to ambient temperature, the reactionmixture was diluted with ethyl acetate (30 mL) and washed with water.The aqueous layer was separated and extracted with ethyl acetate (3×30mL). The combined organics were dried over anhydrous sodium sulfate andconcentrated in vacuo. Purification of the residue by columnchromatography (0% to 5% ethyl acetate in hexanes) afforded the titlecompound (0.426 g, 79%) as a colorless oil: MS (ES+) m/z 369.1 (M−55).

Step 2. Preparation of5-cyclopropyl-4-((1,1-difluoro-6-methylspiro[2.5]-octan-6-yl)-methoxy)-2-fluorobenzoicacid

To a cooled (0° C.) solution of tert-butyl5-cyclopropyl-4-((1,1-difluoro-6-methylspiro[2.5]octan-6-yl)methoxy)-2-fluorobenzoate (0.426 g, 1.00mmol) and anisole (0.155 mL, 1.50 mmol) in dichloromethane (4.5 mL) wasadded trifluoroacetic acid (1.06 mL, 13.5 mmol). The reaction mixturewas stirred at 0° C. for 3 hours before being quenched with water (5mL). The reaction was diluted with dichloromethane (20 mL) and washedwith water (4×10 mL) until the last wash was neutral as monitored by pHpaper. The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to afford the title compound (0.353 g, 95%) as awhite solid: MS (ES−) m/z 367.3 (M−1).

Step 3. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1,1-difluoro-6-methylspiro[2.5]octan-6-yl)methoxy)-2-fluorobenzamide

To a stirred solution of5-cyclopropyl-4-((1,1-difluoro-6-methylspiro[2.5]-octan-6-yl)methoxy)-2-fluorobenzoicacid (0.039 g, 0.106 mmol) in dichloromethane (3 mL) were added1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide hydrochloride (0.031 g,0.159 mmol) and 4-dimethylaminopyridine (0.030 g, 0.244 mmol). Thereaction was stirred at ambient temperature for 10 minutes,azetidine-1-sulfonamide (0.023 g, 0.17 mmol) was added and the stirringwas continued at ambient temperature for 17 hours. The reaction wasconcentrated, diluted with ethyl acetate (10 mL) and washed with 5%aqueous hydrochloric acid solution (5 mL). The organic layer wasseparated, washed with water and brine, dried over anhydrous sodiumsulfate and concentrated in vacuo. Purification of the residue by columnchromatography (0% to 30% ethyl acetate in hexanes) afforded the titlecompound (0.043 g, 83%) as a white solid [mixture of cis/transdiastereomers]: ¹H NMR (300 MHz, CDCl₃) [second diastereomer peaks initalics] δ 8.64 (d, J=16.5 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 6.58[6.56](d, J=14.0 Hz, 1H), 4.24 (t, J=7.7 Hz, 4H), 3.77 [3.72](s, 2H),2.32-2.19 (m, 2H), 2.06-1.94 (m, 1H), 1.82-1.37 (m, 6H), 1.29-1.10 (m,5H), 1.08-0.83 (m, 4H), 0.70-0.60 (m, 2H); MS (ES−) m/z 485.3 (M−1).

Example 270 Synthesis of6-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-cyclopropylnicotinamide

Following the procedure as described in Example 150, step 5 and makingvariations as required to replace methyl sulfonamide withazetidine-1-sulfonamide, the title compound was obtained as a colorlesssolid (0.03 g, 6%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.79 (br s, 1H), 8.49(d, J=2.4 Hz, 1H), 7.74 (d, J=2.4 Hz, 1H), 4.02 (t, J=7.6 Hz, 4H), 3.94(s, 2H), 2.17-2.07 (m, 2H), 2.06-1.99 (m, 1H), 1.98-1.91 (m, 3H),1.73-1.58 (m, 12H), 0.99-0.90 (m, 2H), 0.78-0.72 (m, 2H); MS (ES+) m/z446.2 (M+1).

Example 271 Synthesis of6-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-((2-methoxyethyl)-sulfonyl)nicotinamide

A mixture of 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid (0.24g, 0.73 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.35 g,1.83 mmol), 4-dimethylaminopyridine (0.22 g, 1.83 mmol), and2-methoxyethanesulfonamide (0.13 g, 0.95 mmol) in dichloromethane (10mL) was stirred at ambient temperature for 3 days. The reaction mixturewas diluted with ethyl acetate (50 mL), washed with 1 M aqueoushydrochloric acid solution (2×30 mL), brine (30 mL); dried overanhydrous sodium sulfate; filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (3:1hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the titlecompound (0.25 g, 76%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.97 (br s, 1H),8.45 (d, J=2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 3.93 (s, 2H), 3.75-3.65(m, 4H), 3.14 (s, 3H), 2.07-1.98 (m, 1H), 1.98-1.91 (m, 3H), 1.73-1.58(m, 12H) 0.99-0.91 (m, 2H), 0.76-0.70 (m, 2H); MS (ES+) m/z 449.2 (M+1).

Example 272 Synthesis of6-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-((2-hydroxyethyl)sulfonyl)nicotinamide

A solution of6-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-((2-methoxyethyl)-sulfonyl)nicotinamide(0.19 g, 0.42 mmol) in anhydrous dichloromethane (10 mL) at 0° C. wastreated with boron tribromide (0.079 mL, 0.84 mmol) under nitrogen. Thereaction mixture was stirred for 25 minutes and then diluted with ethylacetate (50 mL). The mixture was washed with 1 M aqueous hydrochloricacid solution (2×30 mL), brine (30 mL); dried over anhydrous sodiumsulfate; filtered and concentrated in vacuo to provide the titlecompound (0.18 g, quant.): ¹H NMR (300 MHz, DMSO-d₆) δ 11.91 (br s, 1H),8.45 (d, J=2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 4.95 (br s, 1H), 3.93(s, 2H), 3.80-3.73 (m, 2H), 3.65-3.58 (m, 2H), 2.07-1.98 (m, 1H),1.98-1.90 (m, 3H), 1.73-1.57 (m, 12H), 0.98-0.90 (m, 2H), 0.76-0.70 (m,2H); MS (ES+) m/z 435.2 (M+1).

Example 273 Synthesis of 6-(adamantan-1-ylmethoxy)-5-cyclopropyl-N—(N-methylsulfamoyl)nicotinamide

A solution of tert-butyl6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinate (0.50 g, 1.30 mmol) indichloromethane (20 mL) was treated with trifluoroacetic acid (5.0 mL).The resulting mixture was stirred for 30 minutes and then concentratedin vacuo. The residue was treated with methanol (20 mL) and concentratedin vacuo. The residue was dissolved in anhydrous tetrahydrofuran (20mL), treated with carbonyl diimidazole (0.42 g, 2.60 mmol), and refluxedunder nitrogen for 30 min. The reaction mixture was cooled to ambienttemperature and added (methylsulfamoyl)amine (0.43 g, 3.90 mmol) and1,8-diazabicycloundec-7-ene (0.58 mL, 3.90 mmol). The reaction mixturewas refluxed under nitrogen for 30 minutes. The reaction mixture wascooled to ambient temperature, diluted with ethyl acetate (50 mL),washed with 1 M aqueous hydrochloric acid solution (2×30 mL) and brine(30 mL); dried over anhydrous sodium sulfate; filtered and concentratedin vacuo. The residue was purified by silica gel column chromatography(2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the titlecompound (0.12 g, 22%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.65 (br s, 1H),8.46 (d, J=2.3 Hz, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.58-7.51 (m, 1H), 3.92(s, 2H), 2.52-2.48 (m, 3H), 2.07-1.98 (m, 1H), 1.97-1.90 (m, 3H),1.72-1.55 (m, 12H), 0.98-0.90 (m, 2H), 0.77-0.70 (m, 2H); MS (ES+) m/z420.2 (M+1).

Example 274 Synthesis of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzamide

Step 1. Preparation of5-chloro-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoic acid

A mixture of (3,5,7-trifluoroadamantan-1-yl)methanol (1.37 g, 6.22 mmol)and potassium tert-butoxide (0.91 g, 8.09 mmol) in anhydrousdimethylsulfoxide (20 mL) was stirred under nitrogen for 20 minutes. Thereaction mixture was treated with a mixture of5-chloro-2,4-difluorobenzoic acid (1.20 g, 6.22 mmol) and potassiumtert-butoxide (0.70 g, 6.22 mmol) in anhydrous dimethylsulfoxide (10 mL)that had been stirred for 10 min. The resulting mixture was stirredunder nitrogen at ambient temperature for 20 hours, diluted with ethylacetate (120 mL), water (20 mL) and 1 M aqueous hydrochloric acidsolution (50 mL). The separated organic layer was washed with 1 Maqueous hydrochloric acid solution (50 mL) and brine; dried overanhydrous sodium sulfate; filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (2:1hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the titlecompound (0.98 g, 40%): ¹H NMR (300 MHz, DMSO-d₆) δ 13.13 (br s, 1H),7.83 (d, J=7.6 Hz, 1H), 7.18 (d, J=12.6 Hz, 1H), 4.00 (s, 2H), 2.25-2.14(m, 3H), 2.06-1.96 (m, 3H), 1.81-1.73 (m, 6H); MS (ES−) m/z 391.2, 393.2(M−1).

Step 2. Preparation of methyl5-chloro-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)-methoxy)benzoate

Following the procedure as described in Example 150 step 2 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-chloronicotinic acid with5-chloro-2-fluoro-4-((−3,5,7-trifluoroadamantan-1-yl)methoxy)benzoicacid, the title compound was obtained as a colorless solid (0.90 g,quant.): ¹H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=7.5 Hz, 1H), 6.62 (d,J=12.0 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 2H), 2.24-2.05 (m, 6H), 1.87-1.78(m, 6H); MS (ES+) m/z 407.3, 409.1 (M+1).

Step 3. Preparation of methyl5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoate

Following the procedure as described in Example 150 step 3 and makingvariations as required to replace methyl6-(adamantan-1-ylmethoxy)-5-chloronicotinate with methyl5-chloro-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoate.Purification by silica gel column chromatography (10:1 hexanes:ethylacetate) gave the title compound as a colorless solid (0.57 g, 62%): ¹HNMR (300 MHz, CDCl₃) 7.49 (d, J=8.2 Hz, 1H), 6.51 (d, J=12.6 Hz, 1H),3.87 (s, 3H), 3.81 (s, 2H), 2.24-2.14 (m, 3H), 2.14-2.04 (m, 3H),1.99-1.88 (m, 1H), 1.86-1.79 (m, 6H), 0.96-0.88 (m, 2H), 0.66-0.58 (m,2H); MS (ES+) m/z 413.2 (M+1).

Step 4. Preparation of5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoicacid

Following the procedure as described in Example 150 step 4 and makingvariations as required to replace methyl6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinate with methyl5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoate,the title compound was obtained as a colorless solid (0.48 g, quant.):MS (ES−) m/z 397.2 (M−1).

Step 5. Preparation of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzamide

Following the procedure as described in Example 150 step 5 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoicacid. Purification by silica gel column chromatography (1:1hexanes:ethyl acetate (+0.2% acetic acid v/v)), gave the title compoundas a colorless solid (0.14 g, 61%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.90(br s, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.94 (d, J=12.9 Hz, 1H), 3.93 (s,2H), 3.31 (s, 3H), 2.25-2.14 (m, 3H), 2.10-1.98 (m, 4H), 1.83-1.75 (m,6H), 0.93-0.85 (m, 2H), 0.66-0.59 (m, 2H); MS (ES−) m/z 474.2 (M−1).

Example 275 Synthesis ofN-(Azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzamide

Following the procedure as described in Example 150 step 5 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoicacid and to replace methyl sulfonamide with azetidine-1-sulfonamide.Purification by silica gel column chromatography (1:1 hexanes:ethylacetate (+0.2% acetic acid v/v)) gave the title compound as a colorlesssolid (0.10 g, 47%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.61 (br s, 1H), 7.14(d, J=8.3 Hz, 1H), 6.94 (d, J=12.7 Hz, 1H), 4.01 (t, J=7.6 Hz, 4H), 3.93(s, 2H), 2.25-1.99 (m, 9H), 1.80 (s, 6H), 0.93-0.85 (m, 2H), 0.67-0.60(m, 2H); MS (ES−) m/z 515.1 (M−1).

Example 276 Synthesis of5-Cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzamide

Following the procedure as described in Example 150 step 5 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoicacid and to replace methyl sulfonamide with cyclopropanesulfonamide.Purification by silica gel column chromatography (1:1 hexanes:ethylacetate (+0.2% acetic acid v/v)) gave the title compound as a colorlesssolid (0.10 g, 79%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.82 (br s, 1H), 7.12(d, J=8.33 Hz, 1H), 6.94 (d, J=12.86 Hz, 1H), 3.93 (s, 2H), 3.09-2.99(m, 1H), 2.25-2.13 (m, 3H), 2.10-1.98 (m, 4H), 1.85-1.75 (m, 6H),1.12-1.01 (m, 4H), 0.93-0.84 (m, 2H), 0.66-0.59 (m, 2H); MS (ES+) m/z502.1 (M+1).

Example 277 Synthesis of5-Chloro-2-fluoro-N-(methylsulfonyl)-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzamide

Following the procedure as described in Example 150 step 5 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with5-chloro-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoic acidand to replace 2-methoxyethanesulfonamide with methyl sulfonamide, thetitle compound was obtained as a colorless solid (0.035 g, 28%): ¹H NMR(300 MHz, DMSO-d₆) δ 12.10 (br s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.20 (d,J=12.28 Hz, 1H), 4.00 (s, 2H), 3.22 (s, 3H), 2.26-2.15 (m, 3H),2.07-1.97 (m, 3H), 1.82-1.74 (m, 6H); MS (ES−) m/z 468.21, 470.20 (M−1).

Example 278 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzamide

Step 1. Preparation of5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzoicacid

Following the procedure as described in Example 274 step 1 and makingvariations as required to replace(3,5,7-trifluoroadamantan-1-yl)methanol withadamantane-1,3-diyldimethanol. Purification by silica gel columnchromatography (1:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gavethe title compound as a colorless solid (3.53 g, 42%): MS (ES−) m/z367.2, 369.2 (M−1).

Step 2. Preparation of methyl 5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzoate

A solution of5-chloro-2-fluoro-4-((3-(hydroxymethyl)adamantan-1-yl)methoxy)benzoicacid (3.53 g, 9.57 mmol), 4-dimethylaminopyridine (0.23 g, 1.90 mmol),and methanol (3.87 mL, 95.70 mmol) in anhydrous dimethylformamide (50mL) under nitrogen was treated with1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (3.67 g, 19.10 mmol). Thereaction mixture was stirred for 24 hours at ambient temperature;diluted with ethyl acetate (200 mL) and washed with water (100 mL),saturated ammonium chloride (100 mL), and brine (100 mL); dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (3:1hexanes:ethyl acetate) to provide the title compound (0.65 g, 18%): ¹HNMR (300 MHz, CDCl₃) δ 7.90 (d, J=7.9 Hz, 1H), 6.59 (d, J=12.6 Hz, 1H),3.85 (s, 3H), 3.56 (s, 2H), 3.23 (s, 2H), 2.11 (br s, 1H), 1.74-1.40 (m,14H); MS (ES+) m/z 383.1, 385.1 (M+1).

Step 3. Preparation of methyl4-((3-(((tert-butyldimethylsilyl)oxy)methyl)-adamantan-1-yl)-methoxy)-5-chloro-2-fluorobenzoate

A solution of methyl5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzoate(0.83 g, 2.17 mmol), tert-butylchlorodimethylsilane (0.36 g, 2.39 mmol),and imidazole (0.74 g, 10.90 mmol) in anhydrous dimethylformamide (12mL) was stirred at ambient temperature under nitrogen for 16 hours. Thereaction mixture was diluted with ethyl acetate (100 mL), washed withwater (50 mL), saturated ammonium chloride (2×50 mL) and brine (2×50mL); dried with anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was purified by silica gel column chromatography (8:1hexanes:ethyl acetate) to provide the title compound (1.10 g, quant): ¹HNMR (300 MHz, CDCl₃) δ 7.93 (d, J=7.6 Hz, 1H), 6.62 (d, J=12.1 Hz, 1H),3.87 (s, 3H), 3.58 (s, 2H), 3.17 (s, 2H), 2.13-2.05 (m, 2H), 1.69-1.58(m, 6H), 1.49-1.36 (m, 6H), 0.87 (s, 9H), −0.01 (s, 6H); MS (ES+) m/z497.1, 499.1 (M+1).

Step 4. Preparation of4-((3-(((tert-butyldimethylsilyl)oxy)methyl)adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoicacid

Following the procedure as described in Example 150 step 4 and makingvariations as required to replace methyl6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinate with methyl4-((3-(((tert-butyldimethylsilyl)oxy)methyl)adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoate,the title compound was obtained as a colorless solid (1.02 g, 94%): ¹HNMR (300 MHz, DMSO-d₆) δ 13.03 (br s, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.12(d, J=12.7 Hz, 1H), 3.70 (s, 2H), 3.12 (s, 2H), 2.05-1.96 (m, 2H),1.63-1.42 (m, 6H), 1.41-1.27 (m, 6H), 0.81 (s, 9H), −0.05 (s, 6H); MS(ES+) m/z 483.1, 485.1 (M+1).

Step 5. Preparation ofN-(azetidin-1-ylsulfonyl)-4-(((((tert-butyldimethyl-silyl)oxy)methyl)adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzamide

Following the procedure as described in Example 150 step 5 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with4-((3-(((tert-butyldimethylsilyl)oxy)methyl)adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzoicacid and to replace methyl sulfonamide with azetidine-1-sulfonamide.Purification by silica gel column chromatography (1:1 hexanes:ethylacetate (+0.2% acetic acid v/v)) gave the title compound as a colorlesssolid (0.82 g, 65%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.78 (br s, 1H), 7.73(d, J=7.5 Hz, 1H), 7.20 (d, J=12.4 Hz, 1H), 4.02 (t J=7.7 Hz, 4H), 3.72(s, 2H), 3.15 (s, 2H), 2.14 (p, J=7.7 Hz, 2H), 2.06-1.98 (m, 2H),1.62-1.46 (m, 6H), 1.43-1.33 (m, 6H), 0.83 (s, 9H), −0.03 (s, 6H); MS(ES+) m/z 601.1, 603.1 (M+1).

Step 6. Preparation ofN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzamide

A solution ofN-(azetidin-1-ylsulfonyl)-4-((3-(((tert-butyldimethylsilyl)oxy)-methyl)adamantan-1-yl)methoxy)-5-chloro-2-fluorobenzamide(0.82 g, 1.36 mmol) in anhydrous tetrahydrofuran (24 mL) was treatedwith tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran,

-   4.1 mL, 4.1 mmol) under nitrogen. The resulting mixture was stirred    for 18 hours; diluted with ethyl acetate (80 mL), washed with 1 M    aqueous hydrochloric acid and brine (80 mL, v/v 1:1) and brine (2×50    mL); dried over anhydrous sodium sulfate; filtered and concentrated    in vacuo. The residue was purified by silica gel column    chromatography (1:1 hexanes:ethyl acetate (+0.2% acetic acid v/v))    to provide the title compound (0.51 g, 77%): ¹H NMR (300 MHz,    DMSO-d₆) δ 11.78 (br s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.20 (d, J=12.5    Hz, 1H), 4.36 (br s, 1H), 4.02 (t, J=7.7 Hz, 4H), 3.72 (s, 2H), 2.99    (s, 2H), 2.14 (p, J=7.7 Hz, 2H), 2.06-1.99 (m, 2H), 1.62-1.46 (m,    6H), 1.44-1.30 (m, 6H); MS (ES+) m/z 486.9, 488.9 (M+1).

Step 7. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzamide

A degassed mixture ofN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((3-(hydroxymethyl)adamantan-1-yl)methoxy)benzamide(0.51 g, 1.04 mmol), cyclopropylboronic acid (0.89 g, 10.4 mmol),tricyclohexylphosphine tetrafluoroborate (0.23 g, 0.62 mmol), potassiumphosphate (tribasic, 1.10 g, 5.20 mmol), water (3.0 mL), andtetrahydrofuran (3.0 mL) in toluene (15 mL) was added palladium (II)acetate (0.070 g, 0.31 mmol). The resulting mixture was refluxed undernitrogen for 18 hours. The reaction mixture was cooled to ambienttemperature and added additional cyclopropylboronic acid (0.89 g, 10.40mmol), tricyclohexylphosphine tetrafluoroborate (0.23 g, 0.62 mmol), andpotassium phosphate (tribasic, 1.10 g, 5.20 mmol), and then refluxedunder nitrogen for 10 hours. The reaction mixture was cooled to ambienttemperature and diluted with ethyl acetate (80 mL) and water (50 mL),acidified with 1 M aqueous hydrochloric acid solution. The organic layerwas washed with 1 M aqueous hydrochloric acid solution (20 mL) and brine(2×50 mL); dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (1:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) toprovide the title compound (0.27 g, 53%): ¹H NMR (300 MHz, DMSO-d₆) δ11.56 (br s, 1H), 7.11 (d, J=8.5 Hz, 1H), 6.90 (d, J=13.0 Hz, 1H),4.38-4.31 (m, 1H), 4.01 (t, J=7.5 Hz, 4H), 3.64 (s, 2H), 3.02-2.96 (m,2H), 2.19-2.06 (m, 2H), 2.06-1.94 M, 3H), 1.64-1.47 (m, 6H), 1.45-1.32(m, 6H), 0.92-0.83 (m, 2H), 0.96-0.61 (m, 2H); MS (ES+) m/z 493.2 (M+1).

Example 279 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((3-(fluoromethyl)adamantan-1-yl)methoxy)benzamide

A solution ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((3-(hydroxymethyl)adamantan-1-yl)methoxy)benzamide(0.27 g, 0.55 mmol) in dichloromethane (15 mL) at ° C. was treated withdiethylaminosulfur trifluoride (0.15 mL, 1.10 mmol) under nitrogen. Theresulting mixture was stirred for 50 minutes and quenched with water(1.0 mL). The mixture was diluted with ethyl acetate (50 mL), washedwith 1 M aqueous hydrochloric acid solution (30 mL) and brine (2×30 mL);dried over anhydrous sodium sulfate; filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (1:1hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the titlecompound (0.019 g, 7%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.56 (br s, 1H),7.13 (d, J=8.5 Hz, 1H), 6.91 (d, J=12.7 Hz, 1H), 4.01 (t, J=7.7 Hz, 4H),3.85-3.45 (m, 4H), 2.19-2.05 (m, 3H), 2.04-1.93 (m, 3H), 1.93-1.83 (m,3H), 1.81-1.61 (m, 4H), 1.56-1.33 (m, 4H), 0.92-0.84 (m, 2H), 0.68-0.61(m, 2H); MS (ES−) m/z 493.2 (M−1).

Example 280 Synthesis of5-chloro-N-(methylsulfonyl)-6-((3,5,7-trifluoroadamantan-1-yl)methoxy)nicotinamide

Step 1. Preparation of5-chloro-6-((3,5,7-trifluoroadamantan-1-yl)methoxy)nicotinic acid

Following the procedure as described in Example 274 step 1 and makingvariations as required to replace 5-chloro-2,4-difluorobenzoic acid with5,6-dichloronicotinic acid. Purification by silica gel columnchromatography (1:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gavethe title compound as a colorless solid (0.93 g, 87%): ¹H NMR (300 MHz,DMSO-d₆) δ 13.33 (br s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.0 Hz,1H), 4.28 (s, 2H), 2.25-2.14 (m, 3H), 2.06-1.96 (m, 3H), 1.81-1.73 (m,6H); MS (ES+) m/z 376.1, 378.1 (M+1).

Step 2. Preparation of5-chloro-N-(methylsulfonyl)-6-((3,5,7-trifluoroadamantan-1-yl)methoxy)nicotinamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with5-chloro-6-((3,5,7-trifluoroadamantan-1-yl)methoxy)nicotinic acid and toreplace 2-methoxyethane- sulfonamide with methyl sulfonamide.Purification by reverse phase HPLC, the title compound was obtained as acolorless solid (0.13 g, 18%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.24 (br s,1H), 8.63 (d, J=2.2 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 4.29 (s, 2H), 3.33(s, 3H), 2.24-2.14 (m, 3H), 2.06-1.96 (m, 3H), 1.81-1.74 (m, 6H); MS(ES−) m/z 451.2, 453.2 (M−1).

Example 281 Synthesis of4-(adamantan-1-ylmethoxy)-3,5-dichloro-N-(methylsulfonyl)benzamide

Step 1. Preparation of 4-(adamantan-1-ylmethoxy)-3,5-dichlorobenzoicacid

Following the procedure as described in Example 274 step 1 and makingvariations as required to replace(3,5,7-trifluoroadamantan-1-yl)methanol with adamantan-1-ylmethanol andto replace 5-chloro-2,4-difluorobenzoic acid with3,5-dichloro-4-fluorobenzoic acid, the title compound was obtained as acolorless solid (1.73 g, quant.): ¹H NMR (300 MHz, DMSO-d₆) δ 13.44 (brs, 1H), 7.86 (s, 2H), 3.53 (s, 2H), 1.99-1.90 (m, 3H), 1.73-1.57 (m,12H); MS (ES−) m/z 353.2, 355.2 (M−1).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-3,5-dichloro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with4-(adamantan-1-ylmethoxy)-3,5-dichlorobenzoic acid and to replace2-methoxyethanesulfonamide with methyl sulfonamide. Purification bysilica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2%acetic acid v/v)) gave the title compound as a colorless solid (0.72 g,74%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.20 (br s, 1H), 8.01 (s, 2H), 3.55(s, 2H), 3.33 (s, 3H), 1.99-1.91 (m, 3H), 1.72-1.57 (m, 12H); MS (ES−)m/z 430.1, 432.1 (M−1).

Example 282 Synthesis of4-((1R,5S,6r)-bicyclo[3.1.0]hexan-6-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of (1R,5S,6r)-methylbicyclo[3.1.0]hexane-6-carboxylate

Following the procedure as described in Example 150 step 2 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-chloronicotinic acid with(1R,5S,6r)-bicyclo[3.1.0]hexane-6-carboxylic acid, the title compoundwas obtained as a colorless oil (0.84 g, 76%): ¹H NMR (300 MHz, CDCl₃) δ3.59 (s, 3H), 1.83-1.64 (m, 6H), 1.61-1.49 (m, 1H), 1.35 (t, J=3.1 Hz,1H), 1.12-0.94 (m, 1H).

Step 2. Preparation of (1R,5S,6r)-bicyclo[3.1.0]hexan-6-ylmethanol

A solution of (1R,5S,6r)-methyl bicyclo[3.1.0]hexane-6-carboxylate (0.84g, 6.00 mmol) and anhydrous methanol (0.49 mL, 12.0 mmol) in anhydroustetrahydrofuran (35 mL) was treated with lithium borohydride (4.0 Msolution in tetrahydrofuran, 3.0 mL, 12.0 mmol). The resulting mixturewas refluxed under nitrogen for 6 hours. The reaction mixture was cooledto ambient temperature and quenched with water (20 mL), acidified with 3M aqueous hydrochloric acid, and diluted with dichloromethane (100 mL).The organic layer was washed with water (20 mL) and brine (30 mL); driedover anhydrous sodium sulfate; filtered and concentrated in vacuo toprovide the title compound (0.58 g, 86%): ¹H NMR (300 MHz, CDCl₃) δ 3.61(br s, 1H), 3.37 (d, J=7.2 Hz, 1H), 1.85-1.45 (m, 6H), 1.14-0.98 (m,2H), 0.90-0.81 (m, 1H).

Step 3. Preparation of4-((1R,5S,6r)-bicyclo[3.1.0]hexan-6-ylmethoxy)-5-chloro-2-fluorobenzoicacid

Following the procedure as described in Example 274 step 1 and makingvariations as required to replace(3,5,7-trifluoroadamantan-1-yl)methanol with(1R,5S,6r)-bicyclo[3.1.0]hexan-6-ylmethanol. Purification by silica gelcolumn chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acidv/v)) gave the title compound as a colorless solid (0.53 g, 36%): ¹H NMR(300 MHz, DMSO-d₆) δ 13.14 (br s, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.09 (d,J=12.9 Hz, 1H), 3.94 (d, J=7.3 Hz, 1H), 1.74-1.57 (m, 4H), 1.55-1.42 (m,1H), 1.32-1.23 (m, 2H), 117-0.99 (m, 2H); MS (ES+) m/z 285.1, 287.1(M+1).

Step 4. Preparation of4-((1R,5S,6r)-bicyclo[3.1.0]hexan-6-ylmethoxy)-5-cyclopropyl-2-fluorobenzoicacid

Following the procedure as described in Example 278 step 7 and makingvariations as required to replaceN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzamide with4-((1R,5S,6r)-bicyclo[3.1.0]hexan-6-ylmethoxy)-5-chloro-2-fluorobenzoicacid. Purification by silica gel column chromatography (2:1hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compoundas a colorless solid (0.076 g, 14%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.70(br s, 1H), 7.24 (d, J=8.5 Hz, 1H), 6.81 (d, J=13.2 Hz, 1H), 3.88 (d,J=7.0 Hz, 2H), 2.06-1.93 (m, 1H), 1.76-1.56 (m, 4H), 1.54-1.43 (m, 1H),1.31-0.98 (m, 4H), 0.92-0.93 (m, 2H), 0.62-0.52 (m, 2H); MS (ES−) m/z289.2 (M−1).

Step 5. Preparation of4-((1R,5S,6r)-bicyclo[3.1.0]hexan-6-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with4-((1R,5S,6r)-bicyclo[3.1.0]hexan-6-ylmethoxy)-5-cyclopropyl-2-fluorobenzoicacid and to replace 2-methoxyethanesulfonamide with methyl sulfonamide.Purification by reverse phase HPLC to give the title compound as acolorless solid (0.025 g, 26%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.84 (br s,1H), 7.06 (d, J=8.5 Hz, 1H), 6.87 (d, J=13.2 Hz, 1H), 3.88 (d, J=7.0 Hz,2H), 3.29 (s, 3H), 2.07-1.97 (m, 1H), 1.75-1.44 (m, 5H), 1.32-1.25 (m,2H), 1.21-0.99 (m, 2H), 0.92-0.83 (m, 2H), 0.70-0.62 (m, 2H); MS (ES−)m/z 366.2 (M−1).

Example 283 Synthesis of4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of tert-butyl4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-chloro-2-fluorobenzoate

A mixture of (1S,2S,4R)-bicyclo[2.2.1]heptan-2-ol (1.0 g, 8.92 mmol),tert-butyl 5-chloro-2,4-difluorobenzoate (2.88 g, 11.60 mmol), andcesium carbonate (5.81 g, 17.84 mmol) in anhydrous dimethylsulfoxide (12mL) was heated in a sealed tube at 80° C. for 18 hours, then at 115° C.for 1 hour. The reaction mixture was cooled to ambient temperature anddiluted with ethyl acetate (80 mL), washed with water (30 mL), saturatedammonium chloride (40 mL) and brine (40 mL); dried over anhydrous sodiumsulfate; filtered and concentrated in vacuo. The residue was trituratedwith methanol to provide the title compound (0.76 g, 25%): ¹H NMR (300MHz, CDCl₃) δ 7.84 (d, J=7.5 Hz, 1H), 6.57 (d, J=12.4 Hz, 1H), 4.22-4.17(m, 1H), 2.51-2.46 (m, 1H), 2.38-2.31 (m, 1H), 1.83-1.67 (m, 2H),1.66-1.58 (m, 1H), 1.56 (s, 9H), 1.52-1.42 (m, 2H), 1.26-1.09 (m, 3H);MS (ES+) m/z 285.0, 287.0 (M-55).

Step 2. Preparation of tert-butyl4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoate

Following the procedure as described in Example 278 step 7 and makingvariations as required to replaceN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzamidewith tert-Butyl4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-chloro-2-fluorobenzoate.Purification by silica gel column chromatography (10:1 hexanes:ethylacetate) gave the title compound as a colorless oil (0.77 g, quant): ¹HNMR (300 MHz, CDCl₃) δ 7.33 (d, J=8.3 Hz, 1H), 6.45 (d, J=13.0 Hz, 1H),4.20-4.13 (m, 1H), 2.49-2.44 (m, 1H), 2.35-2.29 (m, 1H), 2.01-1.91 (m,1H), 1.82-1.73 (m, 1H), 1.70-1.63 (m, 1H), 1.61-1.56 (m, 1H), 1.55 (s,9H), 1.50-1.44 (m, 1H), 1.27-1.09 (m, 4H), 0.88-0.81 (m, 2H), 0.63-0.56(m, 2H); MS (ES+) m/z 291.2 (M-55).

Step 3. Preparation of4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoicacid

A solution of tert-butyl4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoate(0.88 g, 2.54 mmol) in dichloromethane (40 mL) was added trifluoroaceticacid (1.9 mL, 25.4 mmol). The resulting mixture was stirred for 1 hourand then concentrated in vacuo. The residue was triturated with methanolto provide the title compound (0.24 g, 32%): ¹H NMR (300 MHz, DMSO-d₆) δ12.77 (br s, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.78 (d, J=13.2 Hz, 1H),4.40-4.34 (m, 1H), 2.39-2.34 (m, 1H), 2.29-2.23 (m, 1H), 1.99-1.88 (m,1H), 1.85-1.76 (m, 1H), 1.60-1.33 (m, 4H), 1.25-1.03 (m, 3H), 0.88-0.79(m, 2H), 0.57-0.49 (m, 2H); MS (ES+) m/z 291.1 (M+1).

Step 4. Preparation of4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoicacid and to replace 2-methoxyethanesulfonamide with methyl sulfonamide.Purification by silica gel column chromatography (2:1 hexanes:ethylacetate (+0.2% acetic acid v/v)) gave the title compound as a colorlesssolid (0.090 g, 72%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.82 (br s, 1H), 7.09(d, J=8.5 Hz, 1H), 6.84 (d, J=13.2 Hz, 1H), 4.42-4.35 (m, 1H), 3.30 (s,3H), 2.38-2.34 (m, 1H), 2.30-2.24 (m, 1H), 2.00-1.94 (m, 1H), 1.86-1.77(m, 1H), 1.59-1.32 (m, 4H), 1.25-1.04 (m, 3H), 0.88-0.79 (m, 2H),0.66-0.59 (m, 2H); MS (ES−) m/z 368.1 (M+1).

Example 284 Synthesis ofN-(azetidin-1-ylsulfonyl)-4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoicacid and to replace 2-methoxyethanesulfonamide withazetidine-1-sulfonamide. Purification by silica gel columnchromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gavethe title compound as a colorless solid (0.080 g, 56%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.54 (br s, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.85 (d, J=13.1 Hz,1H), 4.42-4.36 (m, 1H), 4.01 (t, J=7.6 Hz, 4H), 2.39-2.34 (m, 1H),2.30-2.45 (m, 1H), 2.19-2.06 (m, 2H), 2.01-1.90 (m, 1H), 1.87-1.77 (m,1H), 1.60-1.32 (m, 4H), 1.26-1.04 (m, 3H), 0.88-0.80 (m, 2H), 0.68-0.59(m, 2H); MS (ES−) m/z 409.2 (M+1).

Example 285 Synthesis of4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of tert-butyl4-((1S,2R,4)-bicyclo[2.2.1]heptan-2-yloxy)-5-chloro-2-fluorobenzoate

Following the procedure as described in Example 283 step 1 and makingvariations as required to replace (1S,2S,4R)-bicyclo[2.2.1]heptan-2-olwith (1S,2R,4R)-bicyclo-[2.2.1]heptan-2-ol. Purification by silica gelcolumn chromatography (R_(f)=0.5 in 10:1 hexanes:ethyl acetate) gave thetitle compound as a colorless oil (0.98 g, 32%): ¹H NMR (300 MHz, CDCl₃)δ 7.84 (d, J=7.9 Hz, 1H), 6.54 (d, J=12.4 Hz, 1H), 4.65-4.57 (m, 1H),2.65-2.59 (m, 1H), 2.33-2.27 (m, 1H), 2.12-1.93 (m, 1H), 1.66-1.59 (m,1H), 1.55 (s, 9H), 1.47-1.29 (m, 4H), 1.18-1.07 (m, 1H); MS (ES+) m/z285.1, 287.1 (M-55).

Step 2. Preparation of tert-butyl4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoate

Following the procedure as described in Example 278 step 7 and makingvariations as required to replaceN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzamidewith tert-butyl4-((1S,2R,4)-bicyclo[2.2.1]heptan-2-yloxy)-5-chloro-2-fluorobenzoate.Purification by silica gel column chromatography (10:1 hexanes:ethylacetate) gave the title compound as a colorless oil (1.00 g, quant): ¹HNMR (300 MHz, CDCl₃) δ 7.35 (d, J=8.5 Hz, 1H), 6.43 (d, J=13.0 Hz, 1H),4.63-4.55 (m, 1H), 2.65-2.58 (m, 1H), 2.32-2.25 (m, 1H), 2.11-1.91 (m,3H), 1.66-1.58 (m, 1H), 1.55 (s, 9H), 1.48-1.29 (m, 4H), 1.15-1.05 (m,1H), 0.92-0.84 (m, 2H), 0.65-0.58 (m, 2H); MS (ES+) m/z 291.2 (M-55).

Step 3. Preparation of4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoicacid

Following the procedure as described in Example 283 step 3 and makingvariations as required to replace tert-butyl4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoatewith tert-butyl4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoate.Purification by silica gel column chromatography (2:1 hexanes:ethylacetate (+0.2% acetic acid v/v)) gave the title compound as a colorlesssolid (0.50 g, 57%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.76 (br s, 1H), 7.27(d, J=8.5 Hz, 1H), 6.76 (d, J=13.2 Hz, 1H), 4.80-4.70 (m, 1H), 2.59-2.52(m, 1H), 2.25-2.18 (m, 1H), 2.15-2.03 (m, 1H), 2.02-1.79 (m, 2H),1.61-1.48 (m, 1H), 1.45-1.17 (m, 4H), 0.97-0.82 (m, 3H), 0.60-0.50 (m,2H); MS (ES+) m/z 291.1 (M+1).

Step 4. Preparation of4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoicacid and to replace 2-methoxyethanesulfonamide with methyl sulfonamide.Purification by silica gel column chromatography (2:1 hexanes:ethylacetate (+0.2% acetic acid v/v)) gave the title compound as a colorlesssolid (0.080 g, 64%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.82 (br s, 1H), 7.10(d, J=8.3 Hz, 1H), 6.83 (d, J=13.1 Hz, 1H), 4.81-4.72 (m, 1H), 3.29 (s,3H), 2.59-2.54 (m, 1H), 2.25-2.19 (m, 1H), 2.17-2.05 (m, 1H), 2.04-1.92(m, 1H), 1.91-1.78 (m, 1H), 1.61-1.48 (m, 1H), 1.46-1.17 (m, 4H),0.97-0.80 (m, 3H), 0.67-0.60 (m, 2H); MS (ES+) m/z 368.09 (M+1).

Example 286 Synthesis ofN-(azetidin-1-ylsulfonyl)-4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoicacid and to replace 2-methoxyethanesulfonamide withazetidine-1-sulfonamide. Purification by silica gel columnchromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gavethe title compound as a colorless solid (0.11 g, 79%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.54 (br s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.84 (d, J=13.1 Hz,1H), 4.82-4.73 (m, 1H), 4.00 (t, J=7.6 Hz, 4H), 2.60-2.54 (m, 1H),2.25-2.19 (m, 1H), 2.18-2.05 (m, 3H), 2.04-1.93 (m, 1H), 1.91-1.80 (m,1H), 1.61-1.49 (m, 1H), 1.46-1.17 (m, 4H), 0.98-0.81 (m, 3H), 0.68-0.60(m, 2H); MS (ES+) m/z 409.1 (M+1).

Example 287 Synthesis of4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoicacid and to replace 2-methoxyethanesulfonamide withcyclopropanesulfonamide. Purification by silica gel columnchromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gavethe title compound as a colorless solid (0.090 g, 67%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.54 (br s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.84 (d, J=13.1 Hz,1H), 4.82-4.73 (m, 1H), 3.08-2.98 (m, 1H), 2.60-2.53 (m, 1H), 2.26-1.18(m, 1H), 2.18-2.05 (m, 1H), 2.03-1.93 (m, 1H), 1.91-1.79 (m, 1H),1.62-1.48 (m, 1H), 1.47-1.18 (m, 4H), 1.12-1.03 (m, 4H), 0.97-0.79 (m,3H), 0.68-0.59 (m, 2H); MS (ES+) m/z 394.1 (M+1).

Example 288 Synthesis of5-chloro-N-(cyclopropylsulfonyl)-4-(((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzamide

Step 1. Preparation of cyclopent-3-en-1-ylmethanol

Following the procedure as described in Example 282 step 2 and makingvariations as required to replace (1R,5S,6r)-methylbicyclo[3.1.0]hexane-6-carboxylate with methylcyclopent-3-enecarboxylate, the title compound was obtained as acolorless oil (4.50 g, 94%): ¹H NMR (300 MHz, CDCl₃) δ 5.62 (s, 2H),3.50 (d, J=5.7 Hz, 2H), 2.52-2.37 (m, 3H), 2.19 (br s, 1H), 2.14-1.99(m, 2H).

Step 2. Preparation of1-((cyclopent-3-en-1-ylmethoxy)methyl)-4-methoxybenzene

A solution of cyclopent-3-en-1-ylmethanol (3.50 g, 35.66 mmol) inanhydrous dimethylformamide (100 mL) at 0° C. was added sodium hydride(60% dispersion in mineral oil, 1.71 g, 42.79 mmol) portionwise undernitrogen. The mixture was stirred at 0° C. for 1 hour and then stirredat ambient temperature for 1 hour. para-Methoxybenzyl chloride (5.80 mL,42.79 mmol) was added to the reaction mixture and the resulting mixturewas stirred for 2 hours. The reaction mixture was quenched with methanol(10 mL) and then water (200 mL). The mixture was extracted with ethylacetate and the organic layer was washed with saturated ammoniumchloride (2×200 mL) and brine (200 mL); dried over anhydrous sodiumsulfate; filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (3:1 hexanes:ethyl acetate) to providethe title compound (6.15 g, 79%): ¹H NMR (300 MHz, CDCl₃) δ 7.26 (d,J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.67-5.60 (m, 2H), 4.44 (s, 2H),3.79 (s, 3H), 3.34 (d, J=7.2 Hz, 2H), 2.66-2.40 (m, 3H), 2.16-2.03 (m,2H); MS (ES+) m/z 241.2 (M+23).

Step 3. Preparation of(1R,3r,5S)-6,6-difluoro-3-(((4-methoxybenzyl)-oxy)methyl)bicyclo[3.1.0]hexaneand(1R,3s,5S)-6,6-difluoro-3-(((4-methoxybenzyl)oxy)methyl)bicyclo[3.1.0]hexane

A mixture of 1-((cyclopent-3-en-1-ylmethoxy)methyl)-4-methoxybenzene(3.18 g, 14.57 mmol) and sodium iodide (4.80 g, 32.05 mmol) in anhydroustetrahydrofuran (24 mL) was added trimethyl(trifluoromethyl)silane (4.3mL, 29.14 mmol). The resulting mixture was heated at 115° C. undermicrowave irradiation in a sealed tube for 1 hour. The reaction mixturewas relieved of gaseous by-products, additionaltrimethyl(trifluoromethyl)silane (4.3 mL, 29.14 mmol) was added, and thereaction mixture was heated at 115° C. under microwave irradiation foranother 1 hour. The reaction mixture was diluted with ethyl acetate (100mL), washed with water (30 mL) and brine (30 mL); dried over anhydroussodium sulfate; filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography to provide two isomers:(1R,3r,5S)-6,6-difluoro-3-(((4-methoxybenzyl)oxy)methyl)bicyclo[3.1.0]hexane(10:1 hexanes:ethyl acetate) (2.64 g, 68%) and(1R,3s,5S)-6,6-difluoro-3-(((4-methoxybenzyl)oxy)methyl)-bicyclo[3.1.0]hexane(0.66 g, 17%). (Stereochemistry was arbitrarily assigned.) Analyticaldata for(1R,3r,5S)-6,6-difluoro-3-(((4-methoxybenzyl)oxy)methyl)bicyclo[3.1.0]hexane:¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz,2H), 4.41 (s, 2H), 3.79 (s, 3H), 3.30 (d, J=6.3 Hz, 2H), 2.36-2.18 (m,1H), 2.12-2.02 (m, 2H), 1.96-1.83 (m, 2H), 1.79-1.65 (m, 2H); ¹⁹F NMR(282 MHz, CDCl₃) δ −124.2 (d, J=158.8 Hz, 1F), −148.0 (d, J=158.8 Hz,1F). Analytical data for(1R,3s,5S)-6,6-difluoro-3-(((4-methoxybenzyl)oxy)methyl)-bicyclo[3.1.0]hexane:¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz,2H), 4.39 (s, 2H), 3.79 (s, 3H), 3.28 (d, J=7.2 Hz, 2H), 2.79-2.60 (m,1H), 2.25-2.11 (m, 2H), 2.07-1.93 (m, 2H), 1.54-1.42 (m, 2H); ¹⁹F NMR(282 MHz, CDCl₃) δ −124.2 (d, J=150.5 Hz, 1F), −151.7 (d, J=150.5 Hz,1F).

Step 4. Preparation of ((1R,3r,5S)-6,6-Difluorobicyclo[3.1.0]hexan-3-yl)methanol

A mixture of (1R,3r,5S)-6,6-difluoro-3-(((4-methoxybenzyl)oxy)-methyl)bicyclo[3.1.0]hexane (2.64 g, 9.84 mmol) and water (1.0 mL) indichloromethane (40 mL) at 0° C. was treated with2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.35 g, 14.76 mmol). Theresulting mixture was stirred for 5 hours and then filtered throughanhydrous sodium sulfate. The filtrate was washed with saturated sodiumbicarbonate (40 mL); dried over anhydrous sodium sulfate; filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (2:1 hexanes:ethyl acetate) to provide the title compound(1.24 g, 85%): ¹H NMR (300 MHz, CDCl₃) δ 3.50 (d, J=6.0 Hz, 2H),2.25-2.11 (m, 1H), 2.11-2.00 (m, 2H), 1.96-1.86 (m, 2H), 1.78-1.64 (m,3H); ¹⁹F NMR (282 MHz, CDCl₃) δ −124.3 (d, J=158.8 Hz, 1F), −148.1 (d,J=158.8 Hz, 1F).

Step 5. Preparation of tert-butyl5-chloro-4-(((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]-hexan-3-yl)methoxy)-2-fluorobenzoate

Following the procedure as described in Example 283 step 1 and makingvariations as required to replace (1S,2S,4R)-bicyclo[2.2.1]heptan-2-olwith ((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]-hexan-3-yl)methanol.Purification by silica gel column chromatography (10:1 hexanes:ethylacetate) gave the title compound as a colorless solid (2.12 g, 67%): ¹HNMR (300 MHz, CDCl₃) δ 7.85 (d, J=7.7 Hz, 1H), 6.58 (d, J=12.3 Hz, 1H),3.90 (d, J=6.1 Hz, 2H), 2.60-2.42 (m, 1H), 2.26-2.14 (m, 2H), 2.04-1.84(m, 4H), 1.55 (s, 9H); MS (ES+) m/z 320.9, 322.9 (M-55).

Step 6. Preparation of5-chloro-4-(((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]-hexan-3-yl)methoxy)-2-fluorobenzoicacid

Following the procedure as described in Example 283 step 3 and makingvariations as required to replace tert-butyl4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoatewith tert-butyl 5-chloro-4-(((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzoate. Purificationby titration with methanol gave the title compound as a colorless solid(0.19 g, 73%): ¹H NMR (300 MHz, DMSO-d₆) δ 13.15 (br s, 1H), 7.81 (d,J=7.7 Hz, 1H), 7.15 (d, J=12.7 Hz, 1H), 4.04 (d, J=6.2 Hz, 2H),2.37-2.21 (m, 1H), 2.18-2.02 (m, 4H), 1.91-1.76 (m, 2H); MS (ES+) m/z321.0, 323.0 (M+1).

Step 7. Preparation of5-chloro-N-(cyclopropylsulfonyl)-4-(((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]-hexan-3-yl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with5-chloro-4-(((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzoicacid and to replace 2-methoxyethanesulfonamide withcyclopropanesulfonamide. Purification by silica gel columnchromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gavethe title compound as a colorless solid (0.090 g, 68%): ¹H NMR (300 MHz,DMSO-d₆) δ 12.01 (br s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.20 (d, J=12.4 Hz,1H), 4.04 (d, J=6.3 Hz, 2H), 3.08-2.98 (m, 1H), 2.37-2.22 (m, 1H),2.17-2.01 (m, 4H), 1.90-1.70 (m, 2H), 1.14-1.02 (m, 4H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −109.6 (s, 1F), −122.5 (d, J=155.7 Hz, 1F), −145.7 (d,J=155.7 Hz, 1F); MS (ES+) m/z 424.0, 426.0 (M+1).

Example 289 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-4-(((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with5-chloro-4-(((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzoicacid and to replace 2-methoxyethanesulfonamide withazetidine-1-sulfonamide. Purification by silica gel columnchromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gavethe title compound as a colorless solid (0.10 g, 79%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.80 (br s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.21 (d, J=12.3 Hz,1H), 4.07-3.97 (m, 6H), 2.38-2.22 (m, 1H), 2.20-2.02 (m, 6H), 1.89-1.76(m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −109.8 (s, 1F), −122.5 (d, J=155.7Hz, 1F), −145.8 (d, J=155.7 Hz, 1F); MS (ES+) m/z 439.0, 441.0 (M+1).

Example 290 Synthesis of5-chloro-N-(cyclopropylsulfonyl)-4-(((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzamide

Step 1. Preparation of((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methanol

Following the procedure as described in Example 288 Step 4 and makingvariations as required to replace(1R,3r,5S)-6,6-difluoro-3-(((4-methoxybenzyl)-oxy)methyl)bicyclo[3.1.0]hexane with(1R,3s,5S)-6,6-difluoro-3-(((4-methoxybenzyl)oxy)-methyl)bicyclo[3.1.0]hexane. Purification by silica gel columnchromatography (2:1 hexanes:ethyl acetate) to give the title compound asa colorless oil (0.37 g, 67%): ¹H NMR (300 MHz, CDCl₃) δ 3.47 (d, J=7.0Hz, 2H), 2.72-2.53 (m, 1H), 2.24-2.11 (m, 2H), 2.07-1.94 (m, 2H), 1.71(br s, 1H), 1.55-1.44 (m, 2H); ¹⁹F NMR (282 MHz, CDCl₃)-124.4 (d,J=151.6 Hz, 1F), −152.2 (d, J=151.6 Hz, 1F).

Step 2. Preparation of tert-butyl 5-chloro-4-(((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzoate

Following the procedure as described in Example 283 step 1 and makingvariations as required to replace (1S,2S,4R)-bicyclo[2.2.1]heptan-2-olwith ((1R,3s,5S)-6,6-Difluorobicyclo[3.1.0]hexan-3-yl)methanol.Purification by silica gel column chromatography (10:1 hexanes:ethylacetate) gave the title compound as a colorless solid (0.37 g, 39%): ¹HNMR (300 MHz, CDCl₃) δ 7.84, (d, J=7.6 Hz, 1H), 6.57 (d, J=12.1 Hz, 1H),3.86 (d, J=7.2 Hz, 2H), 3.06-2.86 (m, 1H), 2.40-2.26 (m, 2H), 2.15-2.00(m, 2H), 1.76-1.60 (m, 2H), 1.55 (s, 9H); MS (ES+) m/z 320.94, 322.92(M−55).

Step 3. Preparation of5-chloro-4-(((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzoicacid

Following the procedure as described in Example 283 step 3 and makingvariations as required to replace tert-butyl4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoatewith tert-butyl 5-chloro-4-(((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzoate. Purificationby titration with methanol gave the title compound as a colorless solid(0.23 g, 74%): ¹H NMR (300 MHz, DMSO-d₆) 13.17 (br s, 1H), 7.80 (d,J=7.7 Hz, 1H), 7.14 (d, J=12.7 Hz, 1H), 3.96 (d, J=6.9 Hz, 2H),2.92-2.76 (m, 1H), 2.30-2.14 (m, 4H), 1.57-1.43 (m, 2H); MS (ES+) m/z321.0, 323.0 (M+1).

Step 4. Preparation of5-chloro-N-(cyclopropylsulfonyl)-4-(((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with5-chloro-4-(((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzoicacid and to replace 2-methoxyethanesulfonamide withcyclopropanesulfonamide. Purification by silica gel columnchromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gavethe title compound as a colorless solid (0.070 g, 53%): ¹H NMR (300 MHz,DMSO-d₆) δ 12.01 (br s, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.20 (d, J=12.4 Hz,1H), 3.97 (d, J=6.9 Hz, 2H), 3.08-2.98 (m, 1H), 2.92-2.78 (m, 1H),2.31-2.15 (m, 4H), 1.57-1.44 (m, 2H), 1.13-1.03 (m, 4H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −109.6 (s, 1F), −122.6 (d, J=147.4 Hz, 1F), −149.5 (d,J=147.4 Hz, 1F); MS (ES+) m/z 424.0, 426.0 (M+1).

Example 291 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-4-(((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with5-chloro-4-(((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzoicacid and to replace 2-methoxyethanesulfonamide withazetidine-1-sulfonamide. Purification by silica gel columnchromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gavethe title compound as a colorless solid (0.10 g, 73%): ¹H NMR (300 MHz,DMSO-d₆) 11.79 (br s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.21 (d, J=12.3 Hz,1H), 4.05-3.94 (m, 6H), 2.94-2.77 (m, 1H), 2.32-2.07 (m, 6H), 1.57-1.45(m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) 5-109.8 (s, 1F), −122.6 (d, J=147.4Hz, 1F), −149.5 (d, J=147.4 Hz, IF); MS (ES+) m/z 439.0, 441.0 (M+1).

Example 292/293 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(((1r,4r)-4-fluoro-4-methylcyclohexyl)methoxy)benzamide andN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(((1s,4s)-4-fluoro-4-methylcyclohexyl)methoxy)benzamide

Step 1. Preparation of (4-fluoro-4-methylcyclohexyl)methanol

A solution of ethyl 4-hydroxy-4-methylcyclohexanecarboxylate (2.50 g,13.42 mmol) in dichloromethane (35 mL) at 0° C. was added withdiethylaminosulfur trifluoride (14.2 mL, 107.40 mmol) slowly undernitrogen. The resulting mixture was stirred for 24 hours. The reactionmixture was diluted with ethyl acetate (100 mL) and poured into ice (200g). The organic layer was washed with saturated sodium bicarbonate(3×100 mL) and brine (100 mL); dried with anhydrous sodium sulfate;filtered and concentrated in vacuo to provide the crude product as anoil; which was dissolved in anhydrous tetrahydrofuran (60 mL) andanhydrous methanol (1.10 mL, 26.8 mmol). To the mixture was addedlithium borohydride (4 M solution in tetrahydrofuran, 6.70 mL, 26.8mmol) dropwise and the resulting mixture was refluxed under nitrogen for4 hours. The reaction mixture was cooled to ambient temperature andquenched with water and then 3 M aqueous hydrochloric acid solution. Themixture was diluted with ethyl acetate (150 mL) and the organic layerwas washed with saturated sodium bicarbonate (2×100 mL) and brine (100mL); dried with anhydrous sodium sulfate; filtered and concentrated invacuo. The residue was purified by silica gel column chromatography (2:1hexanes:ethyl acetate) to provide the title compound as a colorless oil(0.66 g, 34%): ¹H NMR (300 MHz, CDCl₃) δ 3.50-3.43 (m, 2H), 1.97-1.86(m, 1H), 1.85-1.71 (m, 2H), 1.69-1.52 (m, 4H), 1.49-1.24 (m, 5H),1.20-1.03 (m, 1H).

Step 2. Preparation ofN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(((1r,4r)-4-fluoro-4-methylcyclohexyl)methoxy)benzamide andN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(((1s,4s)-4-fluoro-4-methylcyclohexyl)methoxy)benzamide

Following the procedure as described in Example 274 step 1 and makingvariations as required to replace(3,5,7-trifluoroadamantan-1-yl)methanol with(4-fluoro-4-methylcyclohexyl)methanol and to replace5-chloro-2,4-difluorobenzoic acid withN-(azetidin-1-ylsulfonyl)-5-chloro-2,4-difluorobenzamide. Purificationby reverse phase HPLC afforded two isomers:N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(((1s,4s)-4-fluoro-4-methylcyclohexyl)-methoxy)benzamide(first fraction, 0.10 g, 5%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.79 (br s,1H), 7.75 (d, J=7.6 Hz, 1H), 7.23 (d, J=12.4 Hz, 1H), 4.08-3.96 (m, 6H),2.20-2.07 (m, 2H), 1.96-1.68 (m, 5H), 1.66-1.52 (m, 2H), 1.38-1.21 (m,5H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −109.8 (1F), −130.4 (1F); MS (ES+) m/z437.0, 439.0 (M+1). AndN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(((1r,4r)-4-fluoro-4-methylcyclohexyl)-methoxy)benzamide(second fraction, 0.20 g, 10%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.79 (br s,1H), 7.75 (d, J=7.5 Hz, 1H), 7.23 (d, J=12.4 Hz, 1H), 4.07-3.95 (m, 6H),2.21-2.07 (m, 2H), 1.87-1.60 (m, 5H), 1.60-1.43 (m, 2H), 1.42-1.31 (m,2H), 1.67 (d, J=21.2 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −109.8 (1F),−150.0 (1F); MS (ES+) m/z 437.08, 439.08 (M+1).

Example 294 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-(((1r,4r)-4-fluoro-4-methylcyclohexyl)methoxy)benzamide

Following the procedure as described in Example 278 step 7 and makingvariations as required to replaceN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((−3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzamidewithN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(((1r,4r)-4-fluoro-4-methylcyclohexyl)methoxy)benzamide.Purification by silica gel column chromatography (1:1 hexanes:ethylacetate (+0.2% acetic acid v/v)) gave the title compound as a colorlesssolid (0.035 g, 17%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.57 (br s, 1H), 7.10(d, J=8.2 Hz, 1H), 6.93 (d, J=13.0 Hz, 1H), 4.01 (t, J=7.7 Hz, 4H), 3.90(d, J=6.2 Hz, 2H), 2.19-2.06 (m, 2H), 2.04-1.94 (m, 1H), 1.88-1.63 (m,4H), 1.60-1.48 (m, 1H), 1.45-1.28 (m, 4H), 1.22 (d, J=11.0 Hz, 3H),0.90-0.80 (m, 2H), 0.68-0.61 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.5 (1F), −150.1 (1F); MS (ES+) m/z 443.1 (M+1).

Example 295 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-(((1s,4s)-4-fluoro-4-methylcyclohexyl)methoxy)benzamide

Following the procedure as described in Example 278 step 7 and makingvariations as required to replaceN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzamidewithN-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(((1s,4s)-4-fluoro-4-methylcyclohexyl)methoxy)benzamide.Purification by silica gel column chromatography (2:1 hexanes:ethylacetate (+0.2% acetic acid v/v)) gave the title compound as a colorlesssolid (0.018 g, 18%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.57 (br s, 1H), 7.12(d, J=8.2 Hz, 1H), 6.93 (d, J=13.1 Hz, 1H), 4.05-3.92 (m, 6H), 2.19-2.06(m, 2H), 2.03-1.95 (m, 1H), 1.92-1.70 (m, 5H), 1.68-1.53 (m, 2H),1.38-1.18 (m, 5H), 0.90-0.81 (m, 2H), 0.68-0.61 (m, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ −112.5 (1F), −129.7 (1F); MS (ES+) m/z 443.1 (M+1).

Example 296 Synthesis of4-(adamantan-1-ylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of tert-butyl4-(adamantan-1-ylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluorobenzoate

Following the procedure as described in Example 288 step 3 and makingvariations as required to replace1-((cyclopent-3-en-1-ylmethoxy)methyl)-4-methoxybenzene with tert-butyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-vinylbenzoate. Purification bysilica gel column chromatography (10:1 hexanes:ethyl acetate) gave thetitle compound as a colorless solid (0.95 g, 71%): ¹H NMR (300 MHz,CDCl₃) 7.61 (d, J=8.2 Hz, 1H), 6.53 (d, J=12.7 Hz, 1H), 3.57-3.46 (m,2H), 2.74-2.60 (m, 1H), 2.06-1.97 (m, 5H), 1.82-1.60 (m, 12H), 1.55 (s,9H); MS (ES+) m/z 381.1 (M-55).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluorobenzoicacid

Following the procedure as described in Example 283 step 3 and makingvariations as required to replace tert-butyl4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoatewith tert-butyl4-(adamantan-1-ylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluorobenzoate.Purification by trituration with methanol gave the title compound as acolorless solid (0.45 g, 54%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.91 (br s,1H), 7.58 (d, J=8.6 Hz, 1H), 6.94 (d, J=12.7 Hz, 1H), 3.68-3.56 (m, 2H),2.84-2.70 (m, 1H), 1.99-1.90 (m, 4H), 1.89-1.78 (m, 1H), 1.71-1.56 (m,12H); MS (ES+) m/z 381.2 (M+1).

Step 3. Preparation of4-(adamantan-1-ylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with4-(adamantan-1-ylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluorobenzoicacid and to replace 2-methoxyethanesulfonamide with methyl sulfonamide.Purification by silica gel column chromatography (2:1 hexanes:ethylacetate (+0.2% acetic acid v/v)) gave the title compound as a colorlesssolid (0.070 g, 58%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.93 (br s, 1H), 7.45(d, J=8.2 Hz, 1H), 7.00 (d, J=13.0 Hz, 1H), 3.71-3.54 (m, 2H), 3.31 (s,3H), 2.85-2.71 (m, 1H), 2.03-1.87 (m, 5H), 1.75-0.155 (m, 12H); MS (ES+)m/z 458.1 (M+1).

Example 297 Synthesis of4-(adamantan-1-ylmethoxy)-N-(cyclopropylsulfonyl)-5-(2,2-difluoro-cyclopropyl)-2-fluorobenzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with4-(adamantan-1-ylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluorobenzoicacid and to replace 2-methoxyethanesulfonamide withcyclopropylsulfonamide. Purification by silica gel column chromatography(2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the titlecompound as a colorless solid (0.055 g, 43%): ¹H NMR (300 MHz, DMSO-d₆)δ 11.86 (br s, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.00 (d, J=13.0 Hz, 1H),3.70-3.56 (m, 2H), 3.10-2.99 (m, 1H), 2.84-2.71 (m, 1H), 2.04-1.85 (m,5H), 1.76-1.55 (m, 12H), 1.14-1.02 (m, 4H); MS (ES+) m/z 484.1 (M+1).

Example 298 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-(2,2-difluorocyclopropyl)-2-fluorobenzamide

Following the procedure as described in Example 271 and makingvariations as required to replace6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with4-(adamantan-1-ylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluorobenzoicacid and to replace 2-methoxyethanesulfonamide with azetidine1-sulfamide. Purification by silica gel column chromatography (2:1hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compoundas a colorless solid (0.040 g, 31%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.65(br s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.00 (d, J=12.9 Hz, 1H), 4.01 (t,J=7.7 Hz, 4H), 3.68-3.57 (m, 2H), 2.84-2.71 (m, 1H), 2.20-2.06 (m, 2H),2.06-1.88 (m, 5H), 1.75-1.54 (m, 12H); MS (ES+) m/z 499.2 (M+1).

Example 299 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-iodobenzamide

Step 1. Preparation of 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoicacid

To a solution of methyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoate (1.80 g, 4.05 mmol) intetrahydrofuran (10 mL) was added a solution of lithium hydroxidemonohydrate (0.85 g, 20.30 mmol) in water (4 mL) at 0° C. The reactionmixture was allowed to warm to room temperature and stirred for 16hours. After addition of 1 N hydrochloric acid (10 mL) and ethyl acetate(150 mL), the organic phase was separated, washed with 1 N hydrochloricacid (10 mL) and brine (10 mL); dried over anhydrous sodium sulfate, andfiltered. Concentration of the filtrate in vacuo yielded the titlecompound (1.75 g, quant) as an off-white solid, which was used withoutfurther purification: MS (ES−) m/z 429.1 (M−1).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-iodobenzamide

To a mixture of 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid(1.75 g, 4.07 mmol) in anhydrous tetrahydrofuran (20 mL) was added1,1′-carbonyldiimidazole (1.31 g, 8.10 mmol). The resulting mixture washeated at 70° C. for 30 minutes and then cooled to ambient temperature.Azetidine-1-sulfonamide (1.10 g, 8.10 mmol) was added followed by1,8-diazabicyclo-[5.4.0]undec-7-ene (1.72 mL, 12.20 mmol) and thereaction mixture was stirred at ambient temperature for 16 hours. Afteraddition of 1 N hydrochloric acid (5 mL) and diluting the mixture withethyl acetate (150 mL), the organic phase was washed with 1 Nhydrochloride acid (5 mL) and brine (10 mL); dried over anhydrous sodiumsulfate. Filtration and concentration of the filtrate in vacuo gave aresidue which was purified by silica gel column chromatography using0-100% ethyl acetate in hexanes as eluent to afford the title compoundas an off-white solid (0.48 g, 22%): 11H NMR (300 MHz, CDCl₃) δ 8.51 (d,J=8.7 Hz, 1H), 6.56 (d, J=13.7 Hz, 1H), 3.90 (t, J=7.6 Hz, 4H), 3.59 (s,2H), 2.35-2.15 (m, 2H), 2.12-1.99 (m, 3H), 1.83-1.63 (m, 12H); MS (ES−)m/z 547.1 (M−1).

Example 300 Synthesis of4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodo-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace azetidine-1-sulfonamide withmethanesulfonamide and purification by reverse-phase preparative HPLC,the title compound was obtained as a colorless solid (0.037 g, 5%): ¹HNMR (300 MHz, CDCl₃) δ 12.08 (br s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.01(d, J=12.9 Hz, 1H), 3.68 (s, 2H), 3.28 (s, 3H), 2.04-1.95 (m, 3H),1.78-1.60 (m, 12H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −108.9 (s, 1F); MS(ES−) m/z 506.0 (M−1).

Example 301 Synthesis of5-acetyl-4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluorobenzamide

Step 1. Preparation of methyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-(1-hydroxyethyl)benzoate

To a mixture of methyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoate(1.25 g, 2.80 mmol) in anhydrous tetrahydrofuran (10 mL) was addedisopropylmagnesium chloride lithium chloride complex (1.3 M solution intetrahydrofuran, 3.2 mL, 4.20 mmol) at −40° C. The reaction mixture wasstirred for 1 hour at −40° C., after which acetaldehyde (0.79 mL, 14.10mmol) was added. The reaction mixture was allowed to warm to ambienttemperature, stirred for 16 hours and then was quenched by addition ofsaturated ammonium chloride solution (10 mL). The mixture was extractedwith ethyl acetate (2×50 mL) and the combined organic phase was washedwith brine (10 mL), dried over anhydrous sodium sulfate, and filtered.Concentration of the filtrate in vacuo gave a residue which was purifiedby silica gel column chromatography using 0-35% ethyl acetate in hexanesas eluent to afford the title compound as an amorphous solid (0.76 g,75%): ¹H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8.5 Hz, 1H), 6.58 (d, J=12.7Hz, 1H), 5.16-5.06 (m, 1H), 3.88 (s, 3H), 3.55 (d, J=8.9 Hz, 1H), 3.52(d, J=9.3 Hz, 1H), 2.27 (d, J=4.8 Hz, 1H), 2.08-1.98 (m, 3H), 1.83-1.61(m, 12H), 1.49 (d, J=6.5 Hz, 3H); MS (ES+) m/z 345.2 (M−17).

Step 2. Synthesis of methyl5-acetyl-4-(adamantan-1-ylmethoxy)-2-fluorobenzoate

To a mixture of methyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-(1-hydroxyethyl)benzoate (0.76 g,2.10 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane(1.34 g, 3.20 mmol). The reaction mixture was stirred for 1 hour atambient temperature and then quenched by addition of saturated sodiumbicarbonate solution (5 mL) and saturated sodium thiosulfate solution (5mL). Dichloromethane (30 mL) was added and the mixture was stirred for16 hours at ambient temperature. The organic phase was separated, washedwith brine (10 mL), dried over anhydrous sodium sulfate, and filtered.Concentration of the filtrate in vacuo gave a residue, whichre-dissolved in a mixture of diethyl ether and dichloromethane (30 mL,1:1). Insoluble material was filtered off, and the filtrate wasconcentrated in vacuo to yield the title compound as a colorless oil(0.75 g, 99%): ¹H NMR (300 MHz, CDCl₃) δ 8.28 (d, J=8.8 Hz, 1H), 6.62(d, J=12.8 Hz, 1H), 3.78 (s, 3H), 3.55 (s, 2H), 2.55 (s, 3H), 1.97-1.90(m, 3H), 1.72-1.53 (m, 12H).

Step 3. Preparation of5-acetyl-4-(adamantan-1-ylmethoxy)-2-fluorobenzoic acid

To a solution of methyl5-acetyl-4-(adamantan-1-ylmethoxy)-2-fluorobenzoate (0.75 g, 2.10 mmol)in tetrahydrofuran (10 mL) was added a solution of lithium hydroxidemonohydrate (0.441 g, 10.50 mmol) in water (4 mL) at 0° C. The reactionmixture was allowed to warm to ambient temperature and stirred for 16hours. After adjusting the reaction mixture to pH 2 with 1 Nhydrochloric acid, the mixture was extracted with ethyl acetate (3×20mL). The combined organic phase was washed with brine (5 mL), dried overanhydrous sodium sulfate, and filtered. Concentration of the filtrate invacuo yielded the title compound as a colorless oil (0.727 g, quant.),which was used without further purification: MS (ES−) m/z 345.3 (M−1).

Step 4. Preparation of5-acetyl-4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with5-acetyl-4-(adamantan-1-ylmethoxy)-2-fluorobenzoic acid and purificationby triturating in methanol, the title compound was obtained as a beigesolid (0.571 g, 59%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.91 (br s, 1H), 7.97(d, J=8.6 Hz, 1H), 7.24 (d, J=13.0 Hz, 1H), 4.05 (t, J=7.7 Hz, 4H), 3.78(s, 2H), 2.61 (s, 3H), 2.23-2.13 (m, 2H), 2.00 (s, 3H), 1.78-1.61 (m,12H); MS (ES−) m/z 465.0 (M−1).

Example 302 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(2-hydroxypropan-2-yl)benzamide

To a solution of5-acetyl-4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluorobenzamide(0.200 g, 0.43 mmol) in anhydrous tetrahydrofuran (4 mL) was addedmethylmagnesium bromide (3.0 M solution in diethyl ether, 0.29 mL, 0.86mmol) at −78° C. After 1 hour at −78° C., additional methylmagnesiumbromide (3.0 M solution in diethyl ether, 0.29 mL, 0.86 mmol) was added;the reaction mixture was allowed to warm to ambient temperature, andstirred for 1 hour. After addition of 1 N hydrochloride acid (5 mL) anddiluting the mixture with ethyl acetate (100 mL), the organic phase waswashed with brine (5 mL) and dried over anhydrous sodium sulfate.Filtration and concentration of the filtrate in vacuo gave a residuewhich was purified by reverse-phase preparative HPLC to give the titlecompound as a colorless solid (0.101 g, 49%): ¹H NMR (300 MHz, DMSO-d₆)δ 11.63 (br s, 1H), 7.93 (d, J=9.0 Hz, 1H), 6.96 (d, J=13.0 Hz, 1H),5.25 (s, 1H), 4.04 (t, J=7.6 Hz, 4H), 3.65 (s, 2H), 2.22-2.10 (m, 2H),2.01 (br s, 3H), 1.79-1.61 (m, 12H), 1.51 (s, 6H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ −111.6 (s, 1F); MS (ES−) m/z 479.2 (M−1).

Example 303 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(2-fluoropropan-2-yl)benzamide

To a solution of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(2-hydroxypropan-2-yl)benzamide(0.067 g, 0.14 mmol) in anhydrous dichloromethane (10 mL) was addeddiethylaminosulfur trifluoride (22 μL, 0.17 mmol) at −78° C. Thereaction mixture was stirred for 2 hours at −78° C. and then quenched byaddition of saturated sodium bicarbonate solution (5 mL). The mixturewas allowed to warm to ambient temperature and diluted withdichloromethane (50 mL). The organic phase was washed with brine (5 mL),dried over anhydrous magnesium sulfate, and filtered. The residueobtained after concentration of the filtrate in vacuo was purified bysilica gel column chromatography using 0-20% ethyl acetate in hexanes aseluent to afford a beige solid. Lyophilization from acetonitrile andwater (2 mL, 1:1) gave the title compound as colorless solid (0.012 g,18%): ¹H NMR (300 MHz, DMSO-d₆) 11.74 (s, 1H), 7.66 (d, J=8.4 Hz, 1H),7.11 (d, J=12.7 Hz, 1H), 4.05 (t, J=7.6 Hz, 4H), 3.69 (s, 2H), 2.23-2.11(m, 2H), 2.04-1.97 (m, 3H), 1.79-1.61 (m, 18H); ¹⁹F NMR (282 MHz, CDCl₃)6-109.8 (s, 1F), −130.0 (s, 1F); MS (ES−) m/z 481.2 (M−1).

Example 304 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(1-hydroxyethyl)benzamide

Step 1. Preparation of 4-(adamantan-1-ylmethoxy)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorobenzoic acid

To a solution ofmethyl-4-(adamantan-1-ylmethoxy)-2-fluoro-5-(1-hydroxyethyl)benzoate(0.26 g, 0.72 mmol) and 2,6-lutidine (0.17 mL, 1.44 mmol) in anhydrousdichloromethane (5 mL) was added tert-butyldimethylsilyltrifluoromethanesulfonate (0.285 g, 1.08 mmol) at 0° C. The reactionmixture was allowed to warm to ambient temperature and stirred for 1hour. After dilution with dichloromethane (100 mL), the organic phasewas washed with 1 N hydrochloric acid (2×5 mL), brine (10 mL), and driedover anhydrous sodium sulfate. Filtration and concentration of thefiltrate in vacuo afforded methyl4-(adamantan-1-ylmethoxy)-5-(1-((tert-butyldimethylsilyl)-oxy)ethyl)-2-fluorobenzoate as a yellowish oil (0.35 g, quant.), whichwas used without further purification.

To a solution of methyl4-(adamantan-1-ylmethoxy)-5-(1-((tert-butyldimethylsilyl)oxy)-ethyl)-2-fluorobenzoatein tetrahydrofuran (10 mL) was added a solution of lithium hydroxidemonohydrate (0.151 g, 3.6 mmol) in water (5 mL) at 0° C. The reactionmixture was allowed to warm to ambient temperature and stirred for 2days. After adjusting the reaction mixture to pH 5 with 1 N hydrochloricacid, the mixture was extracted with dichloromethane (3×20 mL). Thecombined organic phase was washed with brine (5 mL), dried overanhydrous sodium sulfate, and filtered. Concentration of the filtrate invacuo yielded the title compound as a yellowish oil (0.33 g, quant.),which was used without further purification: MS (ES+) m/z 461.4 (M−1).

Step 4. Preparation of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(1-hydroxyethyl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-(adamantan-1-ylmethoxy)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluoro-benzoicacid,4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-(1-((tert-butyldimethylsilyl)-oxy)ethyl)-2-fluorobenzamide was obtained as an oily residue (0.42 g, quant.), which wasused without further purification.

To a mixture of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorobenzamidein tetrahydrofuran (5 mL) was added 1 N hydrochloric acid (10 mL) andthe reaction mixture was stirred for 16 hours at ambient temperature.After diluting the mixture with dichloromethane (50 mL), the organicphase was separated, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The residue was purified by reverse-phasepreparative HPLC to afford the title compound as a colorless solid(0.073 g, 22%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.66 (br s, 1H), 7.80-7.70(m, 1H), 6.97-6.85 (m, 1H), 5.29-5.16 (m, 1H), 5.01-4.90 (m, 1H),4.15-3.90 (m, 4H), 3.71-3.51 (m, 2H), 3.38-3.29 (m, 2H), 2.23-1.90 (m,3H), 1.80-1.53 (m, 12H), 1.35-1.23 (m, 3H); MS (ES−) m/z 465.2 (M−1).

Example 305/306 Synthesis ofN-(azetidin-1-ylsulfonyl)-4-((4-chlorocyclohex-3-en-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzamide

AndN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-dichlorocyclohexyl)-methoxy)-2-fluorobenzamide

Step 1. Preparation of tert-butyl4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate

To a mixture of 1,4-dioxaspiro[4.5]decan-8-ylmethanol (5.00 g, 29.0mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (7.22 g, 29.00 mmol)in anhydrous dimethyl sulfoxide (30 mL) was added cesium carbonate(18.90 g, 58.00 mmol) and the reaction mixture was heated at 70-80° C.for 4 hours. After cooling to ambient temperature, ethyl acetate wasadded (200 mL) and the mixture was washed with water (4×15 mL), brine(2×15 mL); dried over anhydrous sodium sulfate, and filtered. Afterconcentration of the filtrate in vacuo, the residue was purified bysilica gel column chromatography using 0-30% ethyl acetate in hexanes aseluent to afford the title compound as a colorless oil (5.06 g, 44%): ¹HNMR (300 MHz, CDCl₃) 7.85 (d, J=7.7 Hz, 1H), 6.60 (d, J=12.2 Hz, 1H),3.95-3.93 (m, 4H), 3.83 (d, J=6.3 Hz, 2H), 1.98-1.87 (m, 4H), 1.84-1.71(m, 4H), 1.64-1.56 (m, 1H), 1.56 (s, 9H).

Step 2. Preparation of tert-butyl4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate

To a mixture of tert-butyl4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate (1.20g, 3.00 mmol) in toluene (18 mL) was added cyclopropylboronic acid (1.55g, 18.00 mmol), potassium phosphate tribasic (1.91 g, 9.00 mmol),tricyclohexyl- phosphine tetrafluoroborate (0.884 g, 2.40 mmol),palladium acetate (0.269 g, 1.20 mmol) and water (2 mL). The reactionmixture was thoroughly degassed by passing argon through it and thenheated in a microwave at 150° C. for 30 minutes. The reaction wasperformed 4 times as described. After cooling to ambient temperature,the reaction mixtures were combined, diluted with ethyl acetate (200 mL)and filtered over anhydrous sodium sulfate. After removing all volatilesunder reduced pressure, the residue was purified by silica gel columnchromatography using 0-30% ethyl acetate in hexanes as eluent to affordthe title compound as a yellowish oil (3.16 g, 16%): ¹H NMR (300 MHz,CDCl₃) δ 7.35 (d, J=8.4 Hz, 1H), 6.48 (d, J=12.7 Hz, 1H), 3.95-3.92 (m,4H), 3.80 (d, J=6.1 Hz, 2H), 2.04-1.70 (m, 10H), 1.54 (s, 9H), 0.91-0.82(m, 2H), 0.64-0.57 (m, 2H).

Step 3. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((4-oxocyclohexyl)methoxy)benzoate

To a mixture of tert-butyl4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate(3.16 g, 7.77 mmol) in tetrahydrofuran (10 mL) and water (10 mL) wasadded trifluoroacetic acid (2.7 mL) and the reaction mixture was stirredfor 16 hours at ambient temperature. After diluting the reaction mixturewith ethyl acetate (200 mL), the organic phase was washed with 1 Nsodium hydroxide solution (2×15 mL), brine (15 mL), and dried overanhydrous sodium sulfate. Filtration and concentration of the filtrateunder reduced pressure gave a residue which was purified by silica gelcolumn chromatography using 0-40% ethyl acetate in hexanes as eluent toafford the title compound as a colorless oil (2.70 g, 96%): ¹H NMR (300MHz, CDCl₃) δ 7.37 (d, J=8.4 Hz, 1H), 6.50 (d, J=12.5 Hz, 1H), 3.90 (d,J=6.0 Hz, 2H), 2.53-2.15 (m, 8H), 2.03-1.92 (m, 1H), 1.73-1.59 (m, 1H),1.55 (s, 9H), 0.92-0.83 (m, 2H), 0.65-0.58 (m, 2H).

Step 4. Preparation ofN-(azetidin-1-ylsulfonyl)-4-((4-chlorocyclohex-3-en-1-yl)-methoxy)-5-cyclopropyl-2-fluorobenzamideandN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-dichlorocyclohexyl)methoxy)-2-fluorobenzamide

To a mixture of tert-butyl5-cyclopropyl-2-fluoro-4-((4-oxocyclohexyl)-methoxy)benzoate (0.300 g,0.83 mmol) in anhydrous dichloromethane (5 mL) was added phosphoruspentachloride (0.518 g, 2.49 mmol) at 0° C. The reaction mixture wasallowed to warm to ambient temperature and stirred for 3 hours. Aftercooling to 0° C., water (10 mL) was added to the reaction mixturefollowed by dichloromethane (100 mL). The organic phase was washed withwater (10 mL), brine (10 mL); dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated in vacuo to afford a mixture of4-((4-chlorocyclohex-3-en-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and5-cyclopropyl-4-((4,4-dichlorocyclohexyl)methoxy)-2-fluorobenzoic acidas a colorless oil (0.38 g, quant.) which was used without furtherpurification.

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with a mixture of4-((4-chlorocyclohex-3-en-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and5-cyclopropyl-4-((4,4-dichlorocyclohexyl)methoxy)-2-fluorobenzoic acid,the title compounds were obtained as pure and separated materials afterpurification by reverse-phase preparative HPLC. Data for the firstfraction,N-(azetidin-1-ylsulfonyl)-4-((4-chlorocyclohex-3-en-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzamide,colorless solid (0.041 g, 11%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.61 (br s,1H), 7.14 (d, J=8.3 Hz, 1H), 6.98 (d, J=12.9 Hz, 1H), 5.89-5.84 (m, 1H),4.07-3.98 (m, 6H), 2.45-2.25 (m, 3H), 2.23-1.89 (m, 6H), 1.66-1.51 (m,1H), 0.93-0.86 (m, 2H), 0.72-0.64 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.5 (s, 1F); MS (ES−) m/z 441.2, 443.2 (M−1). Data for secondfraction,N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-dichlorocyclohexyl)methoxy)-2-fluorobenzamide),colorless solid (0.027 g, 7%): ¹H NMR (300 MHz, DMSO-d₆) δ 8.64 (br s,1H), 7.61 (d, J=9.1 Hz, 1H), 6.57 (d, J=14.2 Hz, 1H), 4.24 (t, J=7.5 Hz,4H), 3.89 (d, J=5.8 Hz, 2H), 2.68-2.54 (m, 2H), 2.34-2.18 (m, 4H),2.07-1.86 (m, 4H), 1.82-1.65 (m, 2H), 0.99-0.90 (m, 2H), 0.70-0.63 (m,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −111.1 (s, 1F); MS (ES−) m/z 477.2,479.2 (M−1).

Example 307 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4-cyclopropylcyclohex-3-en-1-yl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 305/306, Step 2 andmaking variations as required to replace tert-butyl4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate withN-(azetidin-1-ylsulfonyl)-4-((4-chlorocyclohex-3-en-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzamideand purification by reverse-phase preparative HPLC, the title compoundwas obtained as a colorless solid (0.031 g, 10%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.60 (br s, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.95 (d, J=12.9 Hz,1H), 5.42 (d, J=3.2 Hz, 1H), 4.02 (t, J=7.7 Hz, 4H), 3.97 (d, J=6.2 Hz,2H), 2.24-2.08 (m, 3H), 2.08-1.93 (m, 2H), 1.93-1.78 (m, 4H), 1.45-1.27(m, 2H), 0.93-0.84 (m, 2H), 0.71-0.63 (m, 2H), 0.54-0.46 (m, 2H),0.45-0.36 (m, 2H); MS (ES−) m/z 447.2 (M−1).

Example 308/309 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-4-(cyclohexyl-d₁₁-methoxy)-2-fluorobenzamide

AndN-(azetidin-1-ylsulfonyl)-4-(cyclohexyl-d₁₁-methoxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 305/306 Step 1 andmaking variations as required to replace1,4-dioxaspiro[4.5]decan-8-ylmethanol with cyclohexyl-d₁₁-methylalcohol, tert-butyl 5-chloro-4-(cyclohexyl-d₁₁-methoxy)-2-fluorobenzoatewas obtained as a colorless oil (2.43 g, 86% yield).

Following the procedure as described in Example 305/306 Step 2 andmaking variations as required to replace tert-butyl4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate withtert-butyl 5-chloro-4-(cyclohexyl-d₁₁-methoxy)-2-fluorobenzoate, amixture of tert-butyl4-(cyclohexyl-d₁₁-methoxy)-5-cyclopropyl-2-fluorobenzoate and tert-butyl5-chloro-4-(cyclohexyl-d₁₁-methoxy)-2-fluorobenzoate was obtained as ayellowish solid (0.482 g). The mixture was used without furtherpurification.

To a mixture of tert-butyl 4-(cyclohexyl-d₃₁-methoxy)-5-cyclopropyl-2-fluorobenzoate and tert-butyl5-chloro-4-(cyclohexyl-di-methoxy)-2-fluorobenzoate (1.57 g) indichloromethane (20 mL) was added trifluoroacetic acid (5 mL). Thereaction mixture was stirred at ambient temperature for 2 hours. Afterevaporation of all volatiles under reduced pressure, a mixture of4-(cyclohexyl-d-methoxy)-5-cyclopropyl-2-fluorobenzoic acid and5-chloro-4-(cyclohexyl-d₁₁-methoxy)-2-fluorobenzoic acid was obtained asa brownish solid (1.30 g).

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with a mixture of4-(cyclohexyl-d₁₁-methoxy)-5-cyclopropyl-2-fluorobenzoic acid and5-chloro-4-(cyclohexyl-d₁₁-methoxy)-2-fluorobenzoic acid, the titlecompounds were obtained as pure and separated materials afterpurification by reverse-phase preparative HPLC. Data for the firstfraction,N-(azetidin-1-ylsulfonyl)-5-chloro-4-(cyclohexyl-d₁₁-methoxy)-2-fluorobenzamide,colorless solid (0.039 g): ¹H NMR (300 MHz, DMSO-d₆) δ 11.83 (br s, 1H),7.77 (d, J=7.5 Hz, 1H), 7.23 (d, J=12.7 Hz, 1H), 4.02 (t, J=7.0 Hz, 4H),3.96 (s, 2H), 2.21-2.09 (m, 2H); MS (ES−) m/z 414.3 (M−1). Data for thesecond fraction,N-(azetidin-1-ylsulfonyl)-4-(cyclohexyl-d₁₁-methoxy)-5-cyclopropyl-2-fluorobenzamide),colorless solid (0.050 g): ¹H NMR (300 MHz, DMSO-d₆) δ 11.60 (br s, 1H),7.13 (d, J=8.3 Hz, 1H), 6.94 (d, J=12.9 Hz, 1H), 4.02 (t, J=7.7 Hz, 4H),3.88 (s, 2H), 2.21-2.09 (m, 2H), 2.07-1.96 (m, 1H), 0.93-0.86 (m, 2H),0.70-0.64 (m, 2H); MS (ES−) m/z 422.2 (M−1).

Example 310 Synthesis of4-(cyclohexyl-d₁₁-methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-(cyclohexyl-d₁₁-methoxy)-5-cyclopropyl-2-fluorobenzoic acid andazetidine-1-sulfonamide with methanesulfonamide, the title compound wasobtained as a colorless solid (0.038 g, 6%) after purification byreverse-phase preparative HPLC: ¹H NMR (300 MHz, DMSO-d₆) δ 11.88 (br s,1H), 7.13 (d, J=8.4 Hz, 1H), 6.93 (d, J=13.1 Hz, 1H), 3.88 (s, 2H), 3.32(s, 3H), 2.08-1.95 (m, 1H), 0.93-0.85 (m, 2H), 0.70-0.63 (m, 2H); MS(ES−) m/z 379.3 (M−1).

Example 311 Synthesis of5-chloro-4-(cyclohexyl-d₁₁-methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with5-chloro-4-(cyclohexyl-d₁₁-methoxy)-2-fluorobenzoic acid andazetidine-1-sulfonamide with methanesulfonamide, the title compound wasobtained as a colorless solid (0.108 g, 26%) after purification byreverse-phase preparative HPLC: ¹H NMR (300 MHz, DMSO-d₆) δ 8.13 (s,1H), 7.77 (d, J=7.5 Hz, 1H), 7.23 (d, J=12.5 Hz, 1H), 3.95 (s, 2H), 3.33(s, 3H); MS (ES−) m/z 373.3, 375.3 (M−1).

Example 312 Synthesis of4-(cyclopentylmethoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replaceazetidine-1-sulfonamide with cyclopropane-sulfonamide, the titlecompound was obtained as a colorless solid (0.039 g, 12%) aftertrituration in diethyl ether followed by trituration in methanol: ¹H NMR(300 MHz, DMSO-d₆) δ 11.81 (br s, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.96 (d,J=13.1 Hz, 1H), 3.97 (d, J=6.8 Hz, 2H), 3.13-3.02 (m, 1H), 2.41-2.26 (m,1H), 2.08-1.95 (m, 1H), 1.85-1.72 (m, 2H), 1.68-1.49 (m, 4H), 1.44-1.31(m, 2H), 1.15-1.07 (m, 4H), 0.93-0.85 (m, 2H), 0.71-0.64 (m, 2H); MS(ES−) m/z 380.2 (M−1).

Example 313 Synthesis of4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluoro-N-((3-methoxyazetidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid andazetidine-1-sulfonamide with 3-methoxyazetidine-1-sulfonamide, the titlecompound was obtained as a colorless solid (0.04 g, 11%) aftertrituration in methanol: ¹H NMR (300 MHz, DMSO-d₆) δ 11.70 (br s, 1H),7.12 (d, J=8.3 Hz, 1H), 6.96 (d, J=13.0 Hz, 1H), 4.24-4.11 (m, 3H),3.99-3.91 (m, 4H), 3.17 (s, 3H), 2.43-2.26 (m, 1H), 2.08-1.95 (m, 1H),1.86-1.73 (m, 2H), 1.69-1.50 (m, 4H), 1.45-1.31 (m, 2H), 0.93-0.85 (m,2H), 0.71-0.64 (m, 2H); MS (ES−) m/z 425.2 (M−1).

Example 314 Synthesis of4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replaceazetidine-1-sulfonamide with 2-methoxyethanesulfonamide, the titlecompound was obtained as a colorless solid (0.039 g, 12%): ¹H NMR (300MHz, DMSO-d₆) δ 11.88 (br s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.93 (d,J=13.0 Hz, 1H), 3.96 (d, J=6.8 Hz, 2H), 3.71 (s, 4H), 3.21 (s, 3H),2.42-2.26 (m, 1H), 2.07-1.96 (m, 1H), 1.86-1.73 (m, 2H), 1.68-1.47 (m,4H), 1.44-1.30 (m, 2H), 0.92-0.84 (m, 2H), 0.70-0.62 (m, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −113.0 (s, 1F); MS (ES−) m/z 398.2 (M−1).

Example 315 Synthesis of4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yloxy)-5-chloro-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)benzamide

Step 1. Preparation of4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yloxy)-5-chloro-2-fluorobenzoic acid

To a mixture of tert-butyl4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yloxy)-5-chloro-2-fluorobenzoate(3.50 g, 10.70 mmol) in dichloromethane (50 mL) was addedtrifluoroacetic acid (10 mL) and the reaction mixture was stirred for 2hours at ambient temperature. After removal of all volatiles underreduced pressure, the residue was purified by silica gel columnchromatography using 0-50% ethyl acetate in hexanes as eluent to affordthe title compound as an off-white solid (2.40 g, 83%): MS (ES−) m/z269.2, 271.3 (M−1).

Step 2. Preparation of4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yloxy)-5-chloro-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yloxy)-5-chloro-2-fluorobenzoic acidand to replace azetidine-1-sulfonamide with3-fluoroazetidine-1-sulfonamide, the title compound was obtained as acolorless solid (0.105 g, 26%) after purification by reverse-phasepreparative HPLC followed by trituration in methanol: ¹H NMR (300 MHz,DMSO-d₆) δ 12.01 (br s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.18 (d, J=12.6 Hz,1H), 5.50-5.22 (m, 1H), 5.10 (t, J=6.4 Hz, 1H), 4.42 (dd, J=10.9, 5.9Hz, 1H), 4.34 (dd, J=10.8, 5.9 Hz, 1H), 4.23 (dd, J=10.9, 3.3 Hz, 1H),4.15 (dd, J=10.7, 3.2 Hz, 1H), 2.32-2.22 (m, 2H), 1.91-1.84 (m, 2H),1.42-1.33 (m, 2H), 0.59-0.44 (m, 2H); MS (ES−) m/z 405.2, 407.2 (M−1).

Example 316 Synthesis ofN-(azetidin-1-ylsulfonyl)-4-((1R,3r,5S)-bicyclo[3.1.0]-hexan-3-yloxy)-5-chloro-2-fluorobenzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yloxy)-5-chloro-2-fluorobenzoicacid, the title compound was obtained as a colorless solid (0.09 mg,23%) after purification by reverse-phase preparative HPLC followed bytrituration in methanol: ¹H NMR (300 MHz, DMSO-d₆) δ 11.80 (br s, 1H),7.77 (d, J=7.5 Hz, 1H), 7.17 (d, J=12.5 Hz, 1H), 5.09 (t, J=6.3 Hz, 1H),4.05 (t, J=7.7 Hz, 4H), 2.33-2.08 (m, 4H), 1.88 (d, J=14.8 Hz, 2H),1.41-1.32 (m, 2H), 0.60-0.44 (m, 2H); MS (ES−) m/z 387.2, 389.2 (M−1).

Example 317 Synthesis of4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yloxy)-5-chloro-2-fluoro-N-(N-methylsulfamoyl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yloxy)-5-chloro-2-fluorobenzoic acidand to replace azetidine-1-sulfonamide with N-methylsulfamide, the titlecompound was obtained as a colorless solid (0.034 g, 9%) afterpurification by reverse-phase preparative HPLC followed byrecrystallization from methanol: ¹H NMR (300 MHz, DMSO-d₆) δ 11.67 (brs, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.69-7.60 (m, 1H), 7.15 (d, J=12.5 Hz,1H), 5.08 (t, J=6.3 Hz, 1H), 2.55 (d, J=4.7 Hz, 3H), 2.32-2.18 (m, 2H),1.87 (d, J=14.8 Hz, 2H), 1.41-1.33 (m, 2H), 0.59-0.43 (m, 2H); MS (ES−)m/z 361.2, 363.2 (M−1).

Example 318 Synthesis of4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yloxy)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yloxy)-5-chloro-2-fluorobenzoic acidand to replace azetidine-1-sulfonamide with methanesulfonamide, thetitle compound was obtained as a colorless solid (0.093 g, 27%) afterpurification by reverse-phase preparative HPLC followed byrecrystallization from methanol: ¹H NMR (300 MHz, DMSO-d₆) δ 12.08 (brs, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.16 (d, J=12.7 Hz, 1H), 5.09 (t, J=6.4Hz, 1H), 3.34 (s, 3H), 2.32-2.20 (m, 2H), 1.87 (d, J=14.8 Hz, 2H),1.41-1.33 (m, 2H), 0.58-0.44 (m, 2H); MS (ES−) m/z 346.2, 348.2 (M−1).

Example 319 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(3-hydroxyoxetan-3-yl)benzamide

Step 1. Preparation of tert-butyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-(3-hydroxyoxetan-3-yl)benzoate

To a solution of tert-butyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoate (0.973 g, 2.00 mmol)in anhydrous tetrahydrofuran (10 mL) was added isopropylmagnesiumchloride lithium chloride complex (1.30 M solution in tetrahydrofuran,1.76 mL, 2.20 mmol) at −40° C. The reaction mixture was stirred for 1hour at −40° C., after which oxetan-3-one (0.432 g, 6.00 mmol) wasadded. The reaction mixture was allowed to warm to ambient temperatureand stirred for 1 hour. After quenched with saturated ammonium chloridesolution (10 mL), the mixture was extracted with ethyl acetate (2×20mL). The combined organic phase was washed with brine (5 mL); dried oversodium sulfate, and filtered. Concentration of the filtrate in vacuogave a residue which was purified by silica gel column chromatographyusing 0-50% ethyl acetate in hexanes as eluent to afford the titlecompound as an amorphous solid (0.336 g, 39%): ¹H NMR (300 MHz, CDCl₃) δ7.75 (d, J=8.2 Hz, 1H), 6.60 (d, J=12.3 Hz, 1H), 5.01 (d, J=6.9 Hz, 2H),4.84 (d, J=7.0 Hz, 2H), 3.86 (s, 1H), 3.52 (s, 2H), 2.05-1.94 (m, 3H),1.78-1.55 (m, 12H), 1.54 (s, 9H).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(3-hydroxyoxetan-3-yl)benzamide

To a solution of tert-butyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-(3-hydroxyoxetan-3-yl)benzoate((330 mg, 0.76 mmol) in dichloromethane (4 mL) was added trifluoroaceticacid (1 mL) and the reaction mixture was stirred for 2 hour at ambienttemperature. Removal of all volatiles in vacuo gave4-(adamantan-1-ylmethoxy)-2-fluoro-5-(3-hydroxyoxetan-3-yl)benzoic acidas an oily residue (0.29 g, quant.).

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-(adamantan-1-ylmethoxy)-2-fluoro-5-(3-hydroxyoxetan-3-yl)benzoic acidand purification by reverse-phase preparative HPLC, the title compoundwas obtained as a colorless solid (0.036 g, 10%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.73 (br s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.03 (d, J=13.0 Hz,1H), 6.14 (s, 1H), 5.02 (d, J=6.6 Hz, 2H), 4.65 (d, J=6.6 Hz, 2H), 4.03(t, J=7.6 Hz, 4H), 3.63 (s, 2H), 2.23-2.09 (m, 2H), 2.02-1.94 (m, 3H),1.79-1.59 (m, 12H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −108.9 (s, 1F); MS(ES−) m/z 493.3 (M−1).

Example 320 Synthesis of4-(adamantan-1-ylmethoxy)-5-bromo-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of 4-(adamantan-1-ylmethoxy)-5-bromo-2-fluorobenzoicacid

A mixture of adamantan-1-ylmethanol (3.51 g, 21.10 mmol) and potassiumtert-butoxide (5.45 g, 48.5 mmol) in anhydrous dimethylsulfoxide (125mL) was stirred for 20 minutes. To the reaction mixture was then added5-bromo-2,4-difluorobenzoic acid (5.00 g, 21.10 mmol) followed byanhydrous dimethylsulfoxide (25 mL). The resulting mixture was stirredfor 18 hours at ambient temperature. The reaction mixture was dilutedwith water (300 mL), and adjusted to pH 3 with 3 M hydrochloric acid.The obtained solid was filtered off and rinsed with water (200 mL) toprovide a 2:1 mixture of the title compound and2-adamantan-1-ylmethoxy)-5-bromo-4-fluorobenzoic acid (6.97 g, 86%).Major isomer: ¹H NMR (300 MHz, DMSO-d₆) δ 7.94 (d, J=7.9 Hz, 1H), 7.05(d, J=12.9 Hz, 1H), 3.65 (s, 2H), 1.98-1.83 (m, 3H), 1.72-1.48 (m, 12H);MS (ES−) m/z 381.13, 383.12 (M−1).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-5-bromo-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-(adamantan-1-ylmethoxy)-5-bromo-2-fluorobenzoic acid and to replaceazetidine-1-sulfonamide with methanesulfonamide, the title compound wasobtained as a colorless solid (1.00 g, 49%): ¹H NMR (300 MHz, DMSO-d₆) δ12.10 (br s, 1H), 7.90 (d, J=7.3 Hz, 1H), 7.17 (d, J=12.4 Hz, 1H), 3.71(s, 2H), 3.35 (s, 3H), 1.98 (br s, 3H), 1.78-1.56 (m, 12H); MS (ES−) m/z458.2, 460.1 (M−1).

Example 321 Synthesis of4-(adamantan-1-ylmethoxy)-2-fluoro-N-((2-hydroxypropyl)sulfonyl)-benzamide

To a solution of4-(adamantan-1-ylmethoxy)-5-bromo-2-fluoro-N-(methylsulfonyl)benzamide(0.340 g, 0.74 mmol) in anhydrous tetrahydrofuran (5 mL) was addedtert-butyllithium (1.7 M solution in pentane, 1.31 mL, 2.22 mmol) at−78° C. The reaction mixture was stirred for 30 minutes at −78° C.followed by addition of acetaldehyde (0.21 mL, 3.70 mmol). The reactionmixture was allowed to warm to ambient temperature and stirred for 16hours. After quenched with 1 N hydrochloric acid (5 mL), the mixture wasdiluted with ethyl acetate (100 mL). The organic phase was washed withbrine (5 mL), dried over anhydrous sodium sulfate, and filtered.Concentration of the filtrate gave a residue which was purified byreverse-phase preparative HPLC to afford the title compound as anoff-white solid (0.075 g, 24%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.79 (s,1H), 7.60 (t, J=8.7 Hz, 1H), 6.93 (dd, J=13.0, 2.2 Hz, 1H), 6.86 (dd,J=8.7, 2.3 Hz, 1H), 5.04 (br s, 1H), 4.17-4.07 (m, 1H), 3.65-3.56 (m,1H), 3.63 (s, 2H), 3.45 (dd, J=14.3, 5.1 Hz, 1H), 2.02-1.94 (m, 3H),1.76-1.57 (m, 12H), 1.20 (d, J=6.3 Hz, 3H); MS (ES−) m/z 424.2 (M−1).

Example 322 Synthesis of4-(adamantan-2-yl(benzyloxy)methyl)-3-chloro-N-(methylsulfonyl)-benzamide

Step 1. Preparation of tert-butyl4-(adamantan-2-yl(hydroxy)methyl)-3-chlorobenzoate

To a solution of tert-butyl 4-bromo-3-chlorobenzoate (0.875 g, 3.00mmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium chloridelithium chloride complex (1.3 M solution in anhydrous tetrahydrofuran,2.78 mL, 3.61 mmol) at −40° C. The reaction was allowed to warm toambient temperature and stirred for 1 hour (solution A). In a separateflask, a solution of spiro(adamantane-2,2′-oxirane) (0.492 g, 3.00 mmol)in anhydrous tetrahydrofuran (5 mL) was treated with boron trifluoridediethyl etherate (0.38 mL, 3.0 mmol) at 0° C. for 30 minutes (solutionB). Solution A was then transferred via cannula to solution B at 0° C.The reaction mixture was allowed to warm to ambient temperature andstirred for 16 hours. After quenched with saturated ammonium chloridesolution (5 mL), the mixture was extracted with ethyl acetate (3×10 mL).The combined organic phase was dried over anhydrous sodium sulfate, andfiltered. Concentration of the filtrate in vacuo gave a residue whichwas purified by silica gel column chromatography using 0-100% ethylacetate in hexanes as eluent to afford the title compound as a colorlesssolid (0.32 g, 33%): ¹H NMR (300 MHz, DMSO-d₆) δ 7.84 (dd, J=8.1, 1.4Hz, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 5.44 (br s,1H), 5.18 (d, J=10.3 Hz, 1H), 2.36-2.29 (m, 1H), 2.06-1.34 (m, 22H),1.08-1.01 (m, 1H); MS (ES+) m/z 359.2, 361.2 (M−17).

Step 2. Preparation of tert-butyl4-(adamantan-2-yl(benzyloxy)methyl)-3-chlorobenzoate

To a solution of tert-butyl4-(adamantan-2-yl(hydroxy)methyl)-3-chlorobenzoate (0.32 mg, 1.00 mmol)in anhydrous dimethylformamide (5 mL) was added sodium hydride (60%dispersion in mineral oil, 0.048 g, 1.2 mmol) at 0° C. The reactionmixture was allowed to warm to ambient temperature and stirred for 1hour. Benzyl bromide (0.24 mL, 2.00 mmol) and tetrabutylammonium iodide(0.037 g, 0.10 mmol) was added and the reaction mixture was stirred for16 hours at ambient temperature. After quenched with saturated ammoniumchloride solution (10 mL), the mixture was diluted with ethyl acetate(150 mL). The organic phase was washed with water (3×10 mL), brine (10mL), dried over anhydrous sodium sulfate, and filtered. Concentration ofthe filtrate in vacuo gave a residue which was purified by silica gelcolumn chromatography using 0-20% ethyl acetate in hexanes as eluent toafford the title compound as a colorless oil (0.437 g, quant.): ¹H NMR(300 MHz, CDCl₃) δ 7.97-7.95 (m, 1H), 7.90 (d, J=8.18 Hz, 1H), 7.60 (d,J=7.39 Hz, 1H), 7.46-7.18 (m, 5H), 5.18-5.11 (m, 1H), 4.30 (d, J=11.54Hz, 1H), 4.18 (d, J=11.60 Hz, 1H), 2.41 (s, 1H), 2.12-1.30 (m, 22H),1.13 (s, 1H).

Step 3. Preparation of4-(adamantan-2-yl(benzyloxy)methyl)-3-chloro-N-(methylsulfonyl)-benzamide

To a mixture of tert-butyl4-(adamantan-2-yl(benzyloxy)methyl)-3-chlorobenzoate (0.43 g, 1.05 mmol)in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL) and thereaction mixture was stirred for 2 hour at ambient temperature. Removalof all volatiles under reduced pressure gave4-(adamantan-2-yl(benzyloxy)methyl)-3-chlorobenzoic acid as an oilyresidue (0.43 g, quant.), which was used without further purification.

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-(adamantan-2-yl(benzyloxy)methyl)-3-chlorobenzoic acid and to replaceazetidine-1-sulfonamide with methanesulfonamide, the title compound wasobtained as a colorless solid (0.312 g, 61%): ¹H NMR (300 MHz, DMSO-d₆)δ 12.24 (br s, 1H), 8.04 (d, J=1.7 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.71(d, J=8.1 Hz, 1H), 7.37-7.22 (m, 5H), 5.08 (d, J=9.9 Hz, 1H), 4.27 (d,J=11.8 Hz, 1H), 4.16 (d, J=11.8 Hz, 1H), 3.37 (s, 3H), 2.38-2.31 (m,1H), 2.09-1.34 (m, 13H), 1.08-1.02 (m, 1H); MS (ES−) m/z 486.2, 488.2(M−1).

Example 323 Synthesis of4-(adamantan-2-yl(hydroxy)methyl)-3-chloro-N-(methylsulfonyl)benzamide

To a mixture of4-(adamantan-2-yl(benzyloxy)methyl)-3-chloro-N-(methylsulfonyl)benzamide(0.290 g, 0.59 mmol) in methanol (10 mL) and ethyl acetate (10 mL) wasadded palladium on carbon (10%, 50 mg) and the reaction mixture wasstirred for 2 hours under an atmosphere of hydrogen. The reactionmixture was filtered over diatomaceous earth, and the filtrate wasconcentrated in vacuo. The obtained residue was purified byreverse-phase preparative HPLC to afford the title compound as acolorless solid (0.065 g, 28%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.20 (br s,1H), 7.94 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.64 (d, J=7.1 Hz, 1H), 5.45(br s, 1H), 5.23-5.14 (m, 1H), 3.31 (s, 3H), 2.37-2.27 (m, 1H),2.11-1.35 (m, 13H), 1.11-1.01 (m, 1H); MS (ES−) m/z 396.2, 398.2 (M−1).

Example 324 Synthesis of5-chloro-4-((4-chlorocyclohex-3-en-1-yl)oxy)-N-(cyclopropylsulfonyl)-2-fluorobenzamide

And5-chloro-N-(cyclopropylsulfonyl)-4-((4,4-dichlorocyclohexyl)oxy)-2-fluorobenzamide

To a mixture of 4,4-dichlorocyclohexanone (WO2011/006794A 1) (5.20 g,31.10 mmol) in anhydrous methanol (100 mL) was added sodium borohydride(2.35 g, 62.20 mmol) at 0° C. The reaction mixture was allowed to warmto ambient temperature and stirred for 1 hour. Concentration in vacuoyielded a residue which was re-dissolved in methanol (50 mL) andconcentrated again in vacuo. The residue was then purified by silica gelcolumn chromatography using 10-100% ethyl acetate in hexanes as eluentto afford 4,4-dichlorocyclohexanol as an orange solid (1.90 g, 36%).

To a mixture of 4,4-dichlorocyclohexanol (1.60 g, 9.50 mmol) inanhydrous dimethyl sulfoxide (15 mL) was added cesium carbonate (6.20 g,19.00 mmol) and the reaction mixture was heated at 70° C. for 16 hours.After cooling to ambient temperature, the reaction mixture was dilutedwith ethyl acetate (200 mL); washed with water (2×20 mL) and brine (10mL); dried over anhydrous sodium sulfate. Filtration and concentrationof the filtrate under reduced pressure gave a residue which was purifiedby silica gel column chromatography using 0-100% ethyl acetate inhexanes as eluent to afford a mixture of tert-butyl2-chloro-4-((4,4-dichlorocyclohexyl)oxy)-5-fluorobenzoate and tert-butyl2-chloro-4-((4-chlorocyclohex-3-en-1-yl)oxy)-5-fluorobenzoate as acolorless oil.

To a mixture of tert-butyl2-chloro-4-((4,4-dichlorocyclohexyl)oxy)-5-fluorobenzoate and tert-butyl2-chloro-4-((4-chlorocyclohex-3-en-1-yl)oxy)-5-fluorobenzoate (0.58 g)in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) and thereaction mixture was stirred at ambient temperature for 2 hours.Concentration in vacuo gave a mixture of2-chloro-4-((4,4-dichlorocyclohexyl)oxy)-5-fluorobenzoic acid and2-chloro-4-((4-chlorocyclohex-3-en-1-yl)oxy)-5-fluorobenzoic acid as asolid residue which was used without further purification.

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace azetidine-1-sulfonamide withcyclopropanesulfonamide and to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with a mixture of2-chloro-4-((4,4-dichlorocyclohexyl)oxy)-5-fluorobenzoic acid and2-chloro-4-((4-chlorocyclohex-3-en-1-yl)oxy)-5-fluorobenzoic acid, thetitle compounds were obtained as pure and separated materials afterpurification by reverse-phase preparative HPLC. Data for the firstfraction,5-chloro-4-((4-chlorocyclohex-3-en-1-yl)oxy)-N-(cyclopropylsulfonyl)-2-fluorobenzamide,colorless solid (0.01 g, 2%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.04 (s, 1H),7.76 (d, J=7.6 Hz, 1H), 7.42 (d, J=12.7 Hz, 1H), 5.79-5.74 (m, 1H),4.97-4.89 (m, 1H), 3.12-3.01 (m, 1H), 2.50-2.23 (m, 4H), 2.04-1.94 (m,2H), 1.17-1.08 (m, 4H); MS (ES−) m/z 406.1, 408.1 (M−1). Data for secondfraction,5-chloro-N-(cyclopropylsulfonyl)-4-((4,4-dichlorocyclohexyl)oxy)-2-fluorobenzamide,colorless solid (0.062 g, 10%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.05 (br s,1H), 7.79 (d, J=7.6 Hz, 1H), 7.41 (d, J=12.6 Hz, 1H), 4.91-4.82 (m, 1H),3.12-3.02 (m, 1H), 2.53-2.39 (m, 4H), 2.07-1.85 (m, 4H), 1.16-1.09 (m,4H); MS (ES+) m/z 444.0, 446.0, 448.0 (M+1).

Example 325 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-(cyclopropyl(hydroxy)-methyl)-2-fluorobenzamide

To a mixture of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-iodobenzamide(0.20 g, 0.36 mmol) in anhydrous tetrahydrofuran (5 mL) was addedisopropylmagnesium chloride lithium chloride complex (1.3 M solution intetrahydrofuran, 0.69 mL, 0.90 mmol) at −40° C. After 1 hour at −40° C.,additional isopropylmagnesium chloride lithium chloride complex (1.3 Msolution in tetrahydrofuran, 0.28 mL, 0.36 mmol) was added, the reactionmixture warmed to 0° C., and stirred for 1 hour.Cyclopropanecarboxaldehyde (excess) was then added, the reaction mixturewas allowed to warm to ambient temperature, and stirred for 16 hours.After quenched with 1 N hydrochloric acid (3 mL), the mixture wasdiluted with ethyl acetate (50 mL). The combined organic phase waswashed with brine (5 mL), dried over anhydrous sodium sulfate, andfiltered. Concentration of the filtrate in vacuo gave a residue whichwas purified by reverse-phase preparative HPLC to afford the titlecompound as a colorless solid (0.015 g, 8%): ¹H NMR (300 MHz, DMSO-d₆) δ11.69 (br s, 1H), 7.73 (d, J=8.7 Hz, 1H), 6.91 (d, J=12.7 Hz, 1H), 5.14(d, J=4.5 Hz, 1H), 4.61 (dd, J=5.7, 4.9 Hz, 1H), 4.02-3.90 (m, 4H), 3.66(d, J=9.3 Hz, 1H), 3.56 (d, J=9.3 Hz, 1H), 2.19-2.06 (m, 2H), 2.03-1.95(m, 3H), 1.76-1.57 (m, 12H), 1.18-1.05 (m, 1H), 0.40-0.25 (m, 4H); MS(ES−) m/z 491.2 (M−1).

Example 326 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-((E)-prop-1-en-1-yl)benzamide

Step 1. Preparation of 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoic acid

Following the procedure as described in Example 305/306 Step 2 andmaking variations as required to replace tert-butyl4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate withtert-butyl 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoate and toreplace cyclopropylboronic acid with trans-propenylboronic acid pinacolester, tert-butyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoate wasobtained as a yellowish oil (1.20 g, quant.). To a mixture of tert-butyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoate (0.30g, 0.75 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid(1 mL) and the reaction mixture was stirred at ambient temperature for 2hours. Concentration in vacuo gave the title compound as a yellowishresidue (0.260 g, quant.) which was used without further purification:MS (ES+) m/z 345.2 (M+1).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-((E)-prop-1-en-1-yl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoic acidand purification by reverse-phase preparative HPLC, the title compoundwas obtained as a colorless solid (0.078 g, 22%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.69 (br s, 1H), 7.72 (d, J=8.4 Hz, 1H), 6.99 (d, J=12.9 Hz,1H), 6.57 (dd, J=16.0, 1.5 Hz, 1H), 6.38 (qd, J=15.8, 6.4 Hz, 1H), 4.05(t, J=7.7 Hz, 4H), 3.65 (s, 2H), 2.23-2.11 (m, 2H), 2.05-1.95 (m, 3H),1.87 (dd, J=6.4, 1.2 Hz, 3H), 1.78-1.60 (m, 12H); MS (ES−) m/z 461.2(M−1).

Example 327 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(trans-2-methylcyclopropyl)benzamide

Step 1. Preparation of4-(adamantan-1-ylmethoxy)-2-fluoro-5-(trans-2-methylcyclopropyl)benzoicacid

To a mixture of diethylzinc (1.0 M solution in heptane, 6.75 mL, 6.75mmol) in anhydrous dichloromethane (2 mL) was added a solution oftrifluoroacetic acid (0.52 mL, 6.80 mmol) in anhydrous dichloromethane(3 mL) at 0° C. and the reaction mixture was stirred for 10 minutes at0° C. A solution of diiodomethane (0.54 mL, 6.75 mmol) indichloromethane (2 mL) was added to the reaction mixture at 0° C. andstirring was continued for 10 minutes at 0° C. To the reaction mixturewas then added a solution of tert-butyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoate (0.90g, 2.25 mmol) in anhydrous dichloromethane (3 mL) at 0° C. The reactionmixture was allowed to warm to ambient temperature and stirred for 4hours. After addition of 1 N hydrochloric acid (10 mL), the mixture wasdiluted with dichloromethane (100 mL). The organic phase was dried overanhydrous sodium sulfate and filtered. Concentration of the filtrategave a residue which was purified by reverse-phase preparative HPLC toafford the title compound as an off-white solid (0.086 g, 11%): MS (ES−)m/z 357.3 (M−1).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(trans-2-methylcyclopropyl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-(adamantan-1-ylmethoxy)-2-fluoro-5-(trans-2-methylcyclopropyl)benzoicacid, the title compound was obtained as a colorless solid (0.055 g,48%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.59 (br s, 1H), 7.15 (d, J=8.3 Hz,1H), 6.92 (d, J=13.0 Hz, 1H), 4.04 (t, J=7.7 Hz, 4H), 3.67 (d, J=9.4 Hz,1H), 3.61 (d, J=9.4 Hz, 1H), 2.22-2.09 (m, 2H), 2.04-1.95 (m, 3H),1.78-1.59 (m, 12H), 1.22 (d, J=7.8 Hz, 3H), 1.16-1.14 (m, 1H), 1.05-0.96(m, 1H), 0.97-0.82 (m, 1H), 0.70-0.62 (m, 1H); MS (ES−) m/z 475.3 (M−1).

Example 328 Synthesis of4-(adamantan-1-ylmethoxy)-2-fluoro-5-(trans-2-(methoxymethyl)-cyclopropyl)-N-(methylsulfonyl)benzamide

Step 1. Preparation of tert-butyl4-(adamantan-1-ylmethoxy)-5-bromo-2-fluorobenzoate

A mixture of 4-(adamantan-1-ylmethoxy)-5-bromo-2-fluorobenzoic acid(6.97 g, 18.19 mmol), di-tert-butyl dicarbonate (7.94 g, 36.38 mmol),and 4-dimethylaminopyridine (0.44 g, 3.64 mmol) in anhydroustetrahydrofuran (50 mL) was stirred at ambient temperature for 18 hours.The reaction mixture was diluted with ethyl acetate (200 mL), washedwith 1 M hydrochloric acid (2×100 mL), brine (2×100 mL), and dried overanhydrous sodium sulfate. Filtration and concentration under reducedpressure gave a residue which was purified by silica gel columnchromatography using 0-50% ethyl acetate in hexanes as eluent followedby trituration in methanol to provide the title compound as a colorlesssolid (1.50 g, 19%): ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, J=8.0 Hz, 1H),6.55 (d, J=12.3 Hz, 1H), 3.53 (s, 2H), 2.05-1.97 (m, 3H), 1.79-1.63 (m,12H, 1.55 (s, 9H); MS (ES+) m/z 439.02, 441.04 (M+1).

Step 2. Preparation of4-(adamantan-1-ylmethoxy)-2-fluoro-5-(trans-2-(methoxymethyl)-cyclopropyl)benzoicacid

To a mixture of tert-butyl4-(adamantan-1-ylmethoxy)-5-bromo-2-fluorobenzoate (1.00 g, 2.28 mmol)in dioxane (15 mL) was added tetrakis(triphenylphosphine)palladium(0.263 g, 0.23 mmol), (E)-3-methoxy-1-propen-1-ylboronic acid, pinacolester (1.36 g, 6.80 mmol), and 2 M sodium bicarbonate solution (4.5 mL,9.00 mmol). The reaction mixture was thoroughly degassed by passingargon through it and then heated in a microwave at 150° C. for 30minutes. After cooling to ambient temperature, the mixture was dilutedwith ethyl acetate (100 mL) and filtered over anhydrous sodium sulfate.Removal of all volatiles under reduced pressure gave a residue which waspurified by silica gel column chromatography using 0-50% ethyl acetatein hexanes as eluent to afford tert-butyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-3-methoxyprop-1-en-1-yl)benzoate(1.17 g, quant.) as a colorless oil.

To a mixture of diethylzinc (1.0 M solution in heptane, 6.8 mL, 6.8mmol) in anhydrous dichloromethane (3 mL) was added a solution oftrifluoroacetic acid (0.52 mL, 6.80 mmol) in anhydrous dichloromethane(2 mL) at 0° C. and the reaction mixture was stirred for 15 minutes at0° C. A solution of diiodomethane (0.55 mL, 6.82 mmol) in anhydrousdichloromethane (2 mL) was added to the reaction mixture at 0° C. andstirring was continued for 15 minutes at 0° C. To the reaction mixturewas then added a solution of tert-butyl4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-3-methoxyprop-1-en-1-yl)benzoate(1.17 g) in dichloromethane (3 mL) at 0° C. The reaction mixture wasallowed to warm to ambient temperature and stirred for 2 hours. Afteraddition of saturated sodium bicarbonate solution (10 mL), the mixturewas diluted with dichloromethane (100 mL). The organic phase was washedwith brine (10 mL) dried over sodium sulfate and filtered. Concentrationof the filtrate in vacuo gave a residue which was treated withtrifluoroacetic acid (2 mL) in dichloromethane (20 mL) for 1 hour. Afterevaporation of all volatiles under reduced pressure, the residue wastriturated with diethyl ether (5 mL) to afford the title compound as acolorless solid (0.554 g, 63%): ¹H NMR (300 MHz, CDCl₃) δ 7.53 (d, J=8.4Hz, 1H), 6.54 (d, J=12.9 Hz, 1H), 3.57 (dd, J=10.3, 6.3 Hz, 1H),3.55-3.48 (m, 2H), 3.37 (s, 3H), 3.36-3.29 (dd, J=10.3, 7.2 Hz, 1H),2.07-1.99 (m, 3H), 1.93 (td, J=8.9, 5.1, 5.1 Hz, 1H), 1.82-1.62 (m,12H), 1.38-1.25 (m, 1H), 1.00 (td, J=8.4, 5.3, 5.3 Hz, 1H), 0.89 (td,J=8.8, 5.2, 5.2 Hz, 1H).

Step 3. Preparation of4-(adamantan-1-ylmethoxy)-2-fluoro-5-(trans-2-(methoxymethyl)-cyclopropyl)-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with4-(adamantan-1-ylmethoxy)-2-fluoro-5-(trans-2-(methoxymethyl)cyclopropyl)benzoicacid and to replace azetidine-1-sulfonamide with methanesulfonamide, thetitle compound was obtained as a colorless solid (0.0678 g, quant.): ¹HNMR (300 MHz, DMSO-d₆) δ 11.89 (br s, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.93(d, J=13.1 Hz, 1H), 3.66 (d, J=9.4 Hz, 1H), 3.61 (d, J=9.5 Hz, 1H),3.46-3.35 (m, 2H), 3.34 (s, 3H), 3.25 (s, 3H), 2.04-1.89 (m, 4H),1.78-1.61 (m, 12H), 1.34-1.22 (m, 1H), 1.06-0.97 (m, 1H), 0.90-0.81 (m,1H); MS (ES−) m/z 464.2 (M−1).

Example 329 Synthesis ofN-(azetidin-1-ylsulfonyl)-3-chloro-4-(3-((2-methylallyl)oxy)-cyclohexyl)-benzamide

Step 1. Preparation of tert-butyl3-chloro-4-(3-hydroxycyclohexyl)benzoate

To a mixture of tert-butyl 4-bromo-3-chlorobenzoate (4.00 g, 13.70 mmol)in anhydrous tetrahydrofuran (40 mL) was added isopropylmagnesiumchloride (1.3 M solution in tetrahydrofuran, 13.8 mL, 17.9 mmol) at −40°C. The reaction mixture was warmed to ambient temperature and stirredfor 1 hour. To this mixture was then added a solution of copper(I)cyanide (1.35 g, 15.10 mmol) and lithium chloride (1.28 g, 30.20 mmol)in anhydrous tetrahydrofuran (5 mL) at 0° C. The reaction mixture wasstirred for 10 minutes at 0° C., then 2-cyclohexen-lone (1.32 mL, 13.70mmol) and trimethylsilyl chloride (1.74 mL, 13.80 mmol) were added tothe reaction mixture. The reaction mixture was stirred for 16 hours atambient temperature. After addition of 1 N hydrochloric acid (10 mL),the reaction mixture was stirred for 1 hour and then diluted with ethylacetate (150 mL). The organic phase was washed with 1 N hydrochloricacid (10 mL), brine (10 mL), and dried over anhydrous sodium sulfate.Filtration and concentration of the filtrate gave tert-butyl3-chloro-4-(3-oxocyclohexyl)benzoate as an oil (4.20 g, quant.), whichwas used without further purification.

To a mixture of tert-butyl 3-chloro-4-(3-oxocyclohexyl)benzoate inanhydrous methanol (50 mL) was added sodium borobydride (1.04 g, 27.40mmol) at 0° C. The reaction mixture was stirred for 1 hour at 0° C.,after which saturated ammonium chloride solution (10 mL) was added. Allvolatiles were evaporated under reduced pressure, and the residue waspartitioned between ethyl acetate (200 mL) and water (20 mL). Theorganic phase was washed with brine (10 mL), dried over sodium sulfate,and filtered. Concentration under reduced pressure gave a residue whichwas purified by silica gel column chromatography using 0-40% ethylacetate in hexanes as eluent to afford the title compound as colorlessoil (2.24 g, 53%): ¹H NMR (300 MHz, CDCl₃) δ 7.94-7.92 (m, 1H),7.84-7.79 (m, 1H), 7.32-7.27 (m, 1H), 3.85-3.69 (m, 1H), 3.16-3.03 (m,1H), 2.19-2.04 (m, 2H), 1.96-1.77 (m, 2H), 1.63-1.18 (m, 14H); MS (ES+)m/z 255.2, 257.1 (M−55).

Step 2. Preparation of 2-methylallyl 3-chloro-4-(3-((2-methylallyl)-oxy)cyclohexyl)benzoate

and tert-butyl 3-chloro-4-(3-hydroxycyclohexyl)benzoate

To a mixture of tert-butyl 3-chloro-4-(3-hydroxycyclohexyl)benzoate(1.10 g, 3.54 mmol) in anhydrous dimethylformamide (15 mL) was addedsodium hydride (60% dispersion in mineral oil, 0.17 g, 4.25 mmol) at 0°C. The reaction mixture was stirred for 1 hour at 0° C. before3-bromo-2-methylpropene (0.71 mL, 7.08 mmol) was added. The reactionmixture was allowed to warm to ambient temperature and stirred for 16hours. After addition of saturated ammonium chloride solution (10 mL)and ethyl acetate (150 mL), the organic phase was washed with water(3×10 mL), brine (10 mL), and dried over sodium sulfate. Filtration andconcentration of the filtrate in vacuo gave a residue which was purifiedby silica gel column chromatography using 0-15% ethyl acetate in hexanesas eluent to afford the title compounds as pure and separated materials.Data for the first fraction, tert-butyl3-chloro-4-(3-hydroxycyclohexyl)benzoate, colorless oil (0.278 g, 21%):¹H NMR (300 MHz, CDCl₃) δ 7.95-7.88 (m, 1H), 7.83-7.77 (m, 1H),7.31-7.25 (m, 1H), 4.94 (s, 1H), 4.83 (s, 1H), 3.91 (s, 2H), 3.46-3.33(m, 1H), 3.11-2.95 (m, 1H), 2.24-2.05 (m, 2H), 1.93-1.74 (m, 2H), 1.70(s, 3H), 1.54 (s, 9H), 1.47-1.14 (m, 4H). Data for the second fraction,2-methylallyl 3-chloro-4-(3-((2-methylallyl)oxy)cyclohexyl)benzoate,colorless oil (0.153 g, 12%): ¹H NMR (300 MHz, CDCl₃) δ 8.02-8.00 (m,1H), 7.91-7.85 (m, 1H), 7.36-7.30 (m, 1H), 5.03 (s, 1H), 4.95 (s, 2H),4.84 (s, 2H), 4.70 (s, 1H), 3.92 (s, 2H), 3.47-3.34 (m, 1H), 3.12-2.99(m, 1H), 2.26-2.08 (m, 2H), 1.95-1.82 (m, 2H), 1.82 (s, 3H), 1.71 (s,3H), 1.48-1.17 (m, 4H).

Step 3. Preparation of3-chloro-4-(3-((2-methylallyl)oxy)cyclohexyl)benzoic acid

To a mixture of 2-methylallyl3-chloro-4-(3-((2-methylallyl)oxy)cyclohexyl)- benzoate (0.153 g, 0.42mmol) in tetrahydrofuran (2 mL) and methanol (1 mL) was added a solutionof lithium hydroxide monohydrate (0.088 g, 2.10 mmol) in water (2 mL).The reaction mixture was stirred for 16 hours at ambient temperature.After dilution with dichloromethane (50 mL), 1N hydrochloric acid (5 mL)was added. The organic phase was dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The title compoundwas obtained as a colorless solid (0.130 g, quant.) and used withoutfurther purification: MS (ES−) m/z 307.2, 309.2 (M−1).

Step 4. Preparation ofN-(azetidin-1-ylsulfonyl)-3-chloro-4-(3-((2-methylallyl)oxy)cyclohexyl)benzamide

Following the procedure as described in Example 299 Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with3-chloro-4-(3-((2-methylallyl)oxy)cyclohexyl)benzoic acid, the titlecompound was obtained as a colorless solid (0.114 g, 64%): ¹H NMR (300MHz, DMSO-d₆) δ 11.90 (br s, 1H), 8.02 (d, J=1.1 Hz, 1H), 7.90 (dd,J=8.2, 1.2 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 4.93 (s, 1H), 4.82 (s, 1H),4.06 (t, J=7.7 Hz, 4H), 3.89 (s, 2H), 3.46-3.29 (m, 1H), 3.09-2.95 (m,1H), 2.24-2.02 (m, 4H), 1.92-1.81 (m, 1H), 1.77-1.68 (m, 1H), 1.67 (s,3H), 1.49-1.12 (m, 4H); MS (ES+) m/z 427.1 (M+1).

Example 330/331 Synthesis ofN-(azetidin-1-ylsulfonyl)-4-((4-chlorocyclohex-3-en-1-yl)oxy)-5-cyclopropyl-2-fluorobenzamide

andN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-dichlorocyclohexyl)-oxy)-2-fluorobenzamide

Step 1. Preparation of tert-butyl4-(1,4-dioxaspiro[4.5]decan-8-yloxy)-5-chloro-2-fluorobenzoate

To a mixture of 1,4-dioxaspiro[4.5]decan-8-ol (2.40 g, 15.20 mmol) andtert-butyl 5-chloro-2,4-difluorobenzoate (3.78 g, 15.20 mmol) inanhydrous dimethyl sulfoxide was added potassium tert-butoxide (2.56 g,22.80 mmol) and the reaction mixture was stirred for 16 hours at ambienttemperature. After dilution with ethyl acetate (200 mL), the organicphase was washed with water (3×10 mL), brine (10 mL), and dried overanhydrous sodium sulfate. Filtration and concentration of the filtrateunder reduced pressure gave a residue which was purified by silica gelcolumn chromatography using 0-30% ethyl acetate in hexanes as eluent toafford the title compound as a colorless oil (0.709 g, 12%): ¹H NMR (300MHz, CDCl₃) δ 7.85 (d, J=7.8 Hz, 1H), 6.64 (d, J=12.3 Hz, 1H), 4.53-4.46(m, 1H), 3.97-3.92 (m, 4H), 2.04-1.58 (m, 8H), 1.55 (d, J=1.0 Hz, 9H).

Step 2. Preparation of tert-butyl4-(1,4-dioxaspiro[4.5]decan-8-yloxy)-5-cyclopropyl-2-fluorobenzoate

Following the procedure as described in Example 305/306, Step 2 andmaking variations as required to replace tert-butyl4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate withtert-butyl4-(1,4-dioxaspiro[4.5]decan-8-yloxy)-5-chloro-2-fluorobenzoate, thetitle compound was obtained as a yellowish oil (0.557 g, 79%): ¹H NMR(300 MHz, CDCl₃) δ 7.36 (d, J=8.4 Hz, 1H), 6.53 (d, J=13.2 Hz, 1H),4.54-4.39 (m, 1H), 3.97-3.93 (m, 4H), 2.07-1.58 (m, 9H), 1.55 (s, 9H),0.92-0.82 (m, 2H), 0.63-0.57 (m, 2H).

Step 3. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoate

To a mixture of tert-butyl4-(1,4-dioxaspiro[4.5]decan-8-yloxy)-5-cyclopropyl-2-fluorobenzoate(0.557 g, 1.44 mmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL) wasadded trifluoroacetic acid (0.5 mL) and the reaction mixture was stirredfor 16 hours at ambient temperature. After addition of dichloromethane(100 mL), the mixture was washed with saturated sodium bicarbonatesolution (10 mL), brine (10 mL), and dried over anhydrous sodiumsulfate. Filtration and concentration of the filtrate in vacuo gave aresidue which was purified by silica gel column chromatography using0-30% ethyl acetate in hexanes as eluent to afford the title compound asa colorless oil (0.300 g, 60%): ¹H NMR (300 MHz, CDCl₃) δ 7.42 (d, J=8.4Hz, 1H), 6.59 (d, J=12.6 Hz, 1H), 4.80-4.71 (m, 1H), 2.77-2.62 (m, 2H),2.42-2.27 (m, 4H), 2.14-1.93 (m, 3H), 1.56 (s, 9H), 0.94-0.84 (m, 2H),0.65-0.60 (m, 2H).

Step 4. Preparation ofN-(azetidin-1-ylsulfonyl)-4-((4-chlorocyclohex-3-en-1-yl)oxy)-5-cyclopropyl-2-fluorobenzamide

andN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-dichlorocyclohexyl)oxy)-2-fluorobenzamide

To a mixture of tert-butyl5-cyclopropyl-2-fluoro-4-((4-oxocyclohexyl)oxy)- benzoate (0.30 g, 0.86mmol) in anhydrous toluene (10 mL) was added phosphorus pentachloride(0.537 g, 2.58 mmol) at 0° C. The reaction mixture was allowed to warmto ambient temperature and stirred for 2 hours. After cooling to 0° C.,water (10 mL) was added to the reaction mixture followed by anhydrousdichloromethane (100 mL). The organic phase was washed with water (5mL), brine (5 mL), dried over sodium sulfate, and filtered. The filtratewas concentrated in vacuo to afford a mixture of4-((4-chlorocyclohex-3-en-1-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acidand 5-cyclopropyl-4-((4,4-dichlorocyclohexyl)oxy)-2-fluorobenzoic acidas a colorless oil (0.40 g, quant.), which was used without furtherpurification.

Following the procedure as described in Example 299, Step 2 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with a mixture of4-((4-chlorocyclohex-3-en-1-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acidand 5-cyclopropyl-4-((4,4-dichlorocyclohexyl)oxy)-2-fluorobenzoic acid,the title compounds were obtained as pure and separated materials afterpurification by reverse-phase preparative HPLC. Data for the firstfraction,N-(azetidin-1-ylsulfonyl)-4-((4-chlorocyclohex-3-en-1-yl)oxy)-5-cyclopropyl-2-fluorobenzamide,colorless solid (0.011 g, 3%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.62 (br s,1H), 7.15 (d, J=7.0 Hz, 1H), 7.11 (d, J=11.8 Hz, 1H), 5.79-5.75 (m, 1H),4.91-4.83 (m, 1H), 4.03 (t, J=7.7 Hz, 4H), 2.48-2.39 (m, 4H), 2.36-2.24(m, 1H), 2.21-2.09 (m, 2H), 2.05-1.92 (m, 2H), 0.91-0.82 (m, 2H),0.70-0.64 (m, 2H); MS (ES−) m/z 427.2, 429.3 (M−1). Data for secondfraction,N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-dichlorocyclohexyl)-oxy)-2-fluorobenzamide), colorless solid (0.058 g, 15%): ¹H NMR (300MHz, DMSO-d₆) δ 11.62 (br s, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.06 (d,J=12.9 Hz, 1H), 4.78 (br s, 1H), 4.12-3.87 (m, 4H), 2.60-2.38 (m, 4H),2.22-1.85 (m, 7H), 0.96-0.84 (m, 2H), 0.69-0.62 (m, 2H); MS (ES−) m/z463.2, 465.2 (M−1).

Example 332 Synthesis of4-((−2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of adamantane-2-carbonitrile

To a solution of 2-adamantanone (6.24 g, 41.50 mmol) in anhydrous1,2-dimethoxyethane (150 mL) was added anhydrous ethanol (3.6 mL, 61.00mmol) and p-toluenesulfonylmethyl isocyanide (10.0 g, 51.50 mmol) at 0°C. Potassium tert-butoxide (7.03 g, 62.70 mmol) was added in portionsover 35 minutes under nitrogen atmosphere. The reaction mixture wasstirred for 3.5 hours at ambient temperature. The mixture was filteredthrough a pad of diatomaceous earth that was washed with ethyl acetate(200 mL). The filtrate was washed with brine (2×200 mL), dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo todryness. The residue was purified by column chromatography with agradient of 0-10% ethyl acetate in hexanes to afford the title compound(5.16 g, 77% yield) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 2.88(s, 1H), 2.15-2.11 (m, 4H), 1.92-1.85 (m, 4H), 1.75-1.70 (m, 6H); MS(ES−) m/z 162.2 (M+1).

Step 2. Preparation of methyl 2-cyanoadamantane-2-carboxylate

To a solution of adamantane-2-carbonitrile (1.17 g, 7.23 mmol) inanhydrous tetrahydrofuran (75 mL) was added lithium diisopropylamide(2.0 M solution in tetrahydrofuran, ethylbenzene and heptanes, 5.4 mL,11.00 mmol)-78° C. The reaction mixture was stirred under a nitrogenatmosphere for 30 minutes, and then methyl chloroformate (0.83 mL, 11.00mmol) was added. After 1.5 hour, the reaction was warmed to ambienttemperature and quenched by addition of 1 M hydrochloric acid (150 mL).The mixture was diluted with ethyl acetate (200 mL), washed with 1 Mhydrochloric acid (150 mL), brine (150 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to dryness. The residue waspurified by column chromatography with a gradient of 0-10% ethyl acetatein hexanes to afford the title compound as a colorless oil (0.95 g,60%): ¹H NMR (300 MHz, CDCl₃) δ 3.80 (s, 3H), 2.51 (br s, 2H), 2.23-2.18(m, 2H), 1.93-1.91 (m, 1H), 1.85-1.71 (m, 9H); MS (ES−) m/z 220.2 (M+1).

Step 3. Preparation of 2-(hydroxymethyl)adamantane-2-carbonitrile

To a solution of methyl 2-cyanoadamantane-2-carboxylate (1.33 g, 6.07mmol) in anhydrous tetrahydrofuran (50 mL) was added anhydrous methanol(0.49 mL, 12 mmol) and lithium borohydride (4.0 M solution intetrahydrofuran, 3.0 mL, 12 mmol). The mixture was heated to refluxunder a nitrogen atmosphere for 7 hours, cooled to ambient temperatureand quenched with careful addition of saturated aqueous ammoniumchloride (10 mL). The mixture was diluted with ethyl acetate (200 mL),washed with a 3:1 mixture of saturated aqueous ammonium chloride andwater (2×200 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to afford the title compound (1.06 g, 91%) as acolorless solid: ¹H NMR (300 MHz, CDCl₃) δ 3.92 (s, 2H), 2.24-2.20 (m,2H), 2.10-1.97 (m, 4H), 1.86-1.84 (m, 5H), 1.73-1.64 (m, 4H); MS (ES−)m/z 192.2 (M+1).

Step 4. Preparation of tert-butyl5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoate

To a solution of 2-(hydroxymethyl)adamantane-2-carbonitrile (0.369 g,1.93 mmol) and tert-butyl-5-chloro-2,4-difluorobenzoate (0.96 g, 3.86mmol) in dimethylsulfoxide (30 mL) was added potassium tert-butoxide(0.42 g, 3.76 mmol). The mixture was stirred at ambient temperature for0.5 hour, then diluted with ethyl acetate (200 mL). The organic layerwas washed with 1 M hydrochloric acid (200 mL), brine (2×150 mL), driedover anhydrous sodium sulfate, filtered and concentrated in vacuo todryness. The residue was purified by column chromatography with agradient of 0-30% ethyl acetate in hexanes to afford the title compound(0.64 g, 79% yield) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 7.88(d, J=7.6 Hz, 1H), 6.65 (d, J=11.7 Hz, 1H), 4.29 (s, 2H), 2.36-2.30 (m,4H), 2.02 (br s, 1H), 1.91-1.74 (m, 9H), 1.56 (s, 9H); MS (ES−) m/z420.1 (M+1).

Step 5. Preparation of tert-butyl4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate

To a solution of tert-butyl5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoate (1.12 g,2.66 mmol) in toluene (40 mL) was added water (5 mL), cyclopropylboronicacid (1.32 g, 15.40 mmol), tribasic potassium phosphate (1.69 g, 7.94mmol), tricyclohexylphosphine tetrafluoroborate (0.658 g, 2.13 mmol) andpalladium(II) acetate trimer (0.25 g, 1.09 mmol) while degassing withargon. The reaction mixture was heated to reflux under an argonatmosphere for 16 hours, cooled to ambient temperature. The mixture wasfiltered through a pad of diatomaceous earth that was washed with ethylacetate (100 mL). The filtrate was diluted with ethyl acetate (100 mL),washed with a 3:1 mixture of saturated aqueous ammonium chloride andwater (150 mL), brine (200 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to dryness. The residue was purifiedby column chromatography with a gradient of 0-10% ethyl acetate inhexanes to afford the title compound as a yellow foamy solid (1.01 g,89%): ¹H NMR (300 MHz, CDCl₃) δ 7.41 (d, J=8.3 Hz, 1H), 6.51 (d, J=12.2Hz, 1H), 4.26 (s, 2H), 2.36-2.27 (m, 4H), 2.08-2.00 (m, 2H), 1.91-1.87(m, 5H), 1.78-1.73 (m, 4H), 1.56 (s, 9H), 0.94-0.87 (m, 2H), 0.64-0.59(m, 2H); MS (ES−) m/z 426.1 (M+1).

Step 6. Preparation of4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid

To a solution of tert-butyl4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate (0.38g, 0.88 mmol) in dichloromethane (30 mL) trifluoroacetic acid (10 mL)was added. The solution was stirred at ambient temperature for 16 hoursand concentrated in vacuo to give the title compound as a pale yellowsolid (0.33 g, quant.): ¹H NMR (300 MHz, DMSO-d₆) δ 12.86 (br s, 1H),7.31 (d, J=8.4 Hz, 1H), 7.09 (d, J=13.0 Hz, 1H), 4.45 (s, 2H), 2.16-1.78(m, 11H), 1.70-1.60 (m, 4H), 0.90-0.84 (m, 2H), 0.60-0.55 (m, 2H); MS(ES−) m/z 468.2 (M−1).

Step 7. Preparation of4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

To a solution of4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid(0.17 g, 0.45 mmol) in anhydrous tetrahydrofuran (5 mL) was added1,1′-carbonyldiimidazole (0.15 g, 0.89 mmol). The reaction solution washeated to reflux under a nitrogen atmosphere for 15 minutes and cooledto ambient temperature. To this reaction solution methanesulfonamide(0.10 g, 1.05 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL,1.40 mmol) was added. The mixture was stirred at ambient temperature for2.5 hours, then diluted with ethyl acetate (10 mL), washed with 1 Mhydrochloric acid (2×10 mL) and brine (2×10 mL). The organic phase wasdried over anhydrous sodium sulfate, filtered and concentrated in vacuoto afford the title compound as a colorless powder (0.019 g, 10%): ¹HNMR (300 MHz, DMSO-d₆) δ 11.94 (br s, 1H), 7.16-7.12 (m, 2H), 4.46 (s,2H), 3.31 (s, 3H), 2.16-1.79 (m, 11H), 1.70-1.61 (m, 4H), 0.90-0.84 (m,2H), 0.69-0.64 (m, 2H); MS (ES−) m/z 445.2 (M−1).

Example 333 Synthesis of4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(N-methylsulfamoyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide with methylsulfamide, the title compound was obtained following trituration withdiethyl ether (10 mL) as a colorless powder (0.11 g, 51%): ¹H NMR (300MHz, DMSO-d₆) δ 11.54 (br s, 1H), 7.57-7.55 (m, 1H), 7.14-7.07 (m, 2H),4.45 (s, 2H), 2.51 (d, J=4.7 Hz, 3H), 2.16-1.79 (m, 11H), 1.70-1.61 (m,4H), 0.89-0.83 (m, 2H), 0.68-0.63 (m, 2H); MS (ES−) m/z 460.2 (M−1).

Example 334 Synthesis ofN-(azetidin-1-ylsulfonyl)-4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide withazetidine-1-sulfonamide, the title compound was obtained followingtrituration with diethyl ether (10 mL) as a colorless powder (0.052 g,22%): ¹H NMR (300 MHz, DMSO-d₆) 11.65 (br, s, 1H), 7.17-7.12 (m, 2H),4.46 (s, 2H), 4.02 (t, J=7.7 Hz, 4H), 2.16-1.93 (m, 10H), 1.87-1.79 (m,3H), 1.70-1.61 (m, 4H), 0.90-0.84 (m, 2H), 0.70-0.64 (m, 2H); MS (ES−)m/z 486.2 (M−1).

Example 335 Synthesis of5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoic acid,the title compound was obtained following trituration with diethyl ether(10 mL) as a colorless powder (0.19 g, 77%): ¹H NMR (300 MHz, DMSO-d₆) δ12.14 (br s, 1H), 7.77 (d, J=7.4 Hz, 1H), 7.40 (d, J=12.3 Hz, 1H), 4.54(s, 2H), 3.32 (s, 3H), 2.15-2.07 (m, 4H), 1.97-1.78 (m, 6H), 1.70-1.60(m, 4H); MS (ES−) m/z 439.1, 441.1 (M−1).

Example 336 Synthesis of5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluoro-N-(N-methylsulfamoyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide with methylsulfamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoic acid,the title compound was obtained following trituration with diethyl ether(10 mL) as a colorless powder (0.073 g, 52%): ¹H NMR (300 MHz, DMSO-d₆)δ 11.72 (s, 1H), 7.73-7.66 (m, 2H), 7.34 (d, J=12.2 Hz, 1H), 4.54 (s,2H), 2.53 (d, J=4.6 Hz, 3H), 2.15-2.07 (m, 4H), 1.97-1.78 (m, 6H),1.70-1.60 (m, 4H); MS (ES−) m/z 454.1, 456.1 (M−1).

Example 337 Synthesis of5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide with2-methoxyethanesulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoic acid,the title compound was obtained following trituration with a 5:1 mixtureof hexanes in diethyl ether (10 mL) as a colorless powder (0.094 g,63%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.13 (br s, 1H), 7.70 (d, J=7.4 Hz,1H), 7.40 (d, J=12.2 Hz, 1H), 4.54 (s, 2H), 3.70 (s, 4H), 3.18 (s, 3H),2.15-2.07 (m, 4H), 1.97-1.78 (m, 6H), 1.70-1.60 (m, 4H); MS (ES−) m/z483.2, 485.2 (M−1).

Example 338 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-4-((2-cyanoadamantan-2-yl)-methoxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide withazetidine-1-sulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoic acid,the title compound was obtained following purification by reverse-phaseHPLC as a colorless powder (0.037 g, 18%): ¹H NMR (300 MHz, DMSO-d₆) δ11.86 (br s, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.41 (d, J=12.2 Hz, 1H), 4.54(s, 2H), 4.02 (t, J=7.7, 7.7 Hz, 4H), 2.17-2.07 (m, 6H), 1.98-1.78 (m,6H), 1.70-1.61 (m, 4H); MS (ES−) m/z 480.1, 482.1 (M−1).

Example 339 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-4-((cyclohexyloxy)methyl)-2-fluorobenzamide

Step 1. Preparation of1-bromo-5-chloro-4-(cyclohexyloxymethyl)-2-fluorobenzene

To a solution of (4-bromo-2-chloro-5-fluorophenyl)methanol (5.00 g,21.00 mmol) in dichloromethane (150 mL) was added phosphorous tribromide(8.53 g, 31.50 mmol) at 0° C. The clear reaction solution was stirred atthe same temperature for 1 hour, then at an ambient temperature for 2hours. The reaction mixture was concentrated in vacuo to dryness toobtain viscous yellow liquid which was added to a stirred mixture ofcyclohexanol (1.68 g, 16.80 mmol) and sodium hydride (60% dispersion inmineral oil, 1.93 g, 21.00 mmol,) in N,N-dimethylformamide (15 mL) at 0°C. The reaction mixture was stirred at ambient temperature for 16 hoursand quenched with addition of saturated ammonium chloride (100 mL). Theorganic layer was extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over anhydrous sodium sulfate and filtered thesolid. The filtrate was concentrated in vacuo to dryness. The residuewas purified by flash column chromatography with ethyl acetate inhexanes (10%) to afford the title compound (2.60 g, 38%) as a viscousliquid: MS (ES+) m/z 320.9, 318.9 (M+1).

Step 2. Preparation of tert-butyl5-chloro-4-(cyclohexyloxymethyl)-2-fluorobenzoate

To a solution of1-bromo-5-chloro-4-(cyclohexyloxymethyl)-2-fluorobenzene (2.60 g, 8.13mmol) in tetrahydrofuran (100 mL) was added a solution ofisopropylmagnesium chloride (8.1 mL, 16.3 mmol, 2.0 M solution intetrahydrofuran) at 0° C. The reaction mixture was stirred at the sametemperature for 0.5 h, then added a solution of di-tert-butyldicarbonate (3.54 g, 16.3 mmol) in tetrahydrofuran (10 mL). The mixturewas stirred at an ambient temperature for 16 h, then diluted with ethylacetate (100 mL) and washed with saturated ammonium chloride (3×50 mL),brine (3×50 mL), dried over anhydrous sodium sulfate and filtered thesolid. The filtrate was concentrated in vacuo to dryness to afford thetitle compound (1.86 g, 65%) as a pale yellow gum which was directlysubjected to next step without any further purification: MS (ES+) m/z342.1, 344.1 (M+23).

Step 3. 5-chloro-4-(cyclohexyloxymethyl)-2-fluorobenzoic acid

To a solution of tert-butyl5-chloro-4-(cyclohexyloxymethyl)-2-fluorobenzoate (1.86 g, 5.43 mmol) indichloromethane (50 mL) was added trifluoroacetic acid (20 mL). Thereaction solution was stirred at ambient temperature for 3 hours, thenconcentrated under reduced pressure. The residue was diluted with ethylacetate (50 mL), washed with brine (3×25 mL), dried over anhydroussodium sulfate, filtered the solid. The filtrate was concentrated invacuo to dryness to afford the title compound (0.50 g, 32% crude yield)which was subjected to next step without any further purification: MS(ES+) m/z 287.0, 285.0 (M+1).

Step 4. Preparation ofN-(azetidin-1-ylsulfonyl)-5-chloro-4-((cyclohexyloxy)-methyl)-2-fluorobenzamide

To a solution of 5-chloro-4-(cyclohexyloxymethyl)-2-fluorobenzoic acid(0.12 g, 0.42 mmol) in anhydrous tetrahydrofuran (5 mL) was added1,1′-carbonyldiimidazole (0.088 g, 0.55 mmol). The reaction solution washeated to reflux under a nitrogen atmosphere for 15 minutes and cooledto ambient temperature. To this solution was addedazetidine-1-sulfonamide (0.086 g, 63 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 g, 1.05 mmol). The mixture wasstirred at ambient temperature for 16 hours, then diluted with ethylacetate (15 mL) and washed with 1 M hydrochloric acid (2×10 mL) andbrine (2×10 mL). The organic phase was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to dryness. The residue waspurified by reverse-phase preparative HPLC to afford the title compound(0.005 g, 3%) as a colorless powder: MS (ES+) m/z 405.1, 407.1 (M+H)

Example 340 Synthesis of5-chloro-4-((cyclohexyloxy)methyl)-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 339 Step 4 and makingnon-critical variations to replace azetidine-1-sulfonamide withcyclopropanesulfonamide, the title compound was obtained (0.005 g, 3%)as a colourless solid: MS (ES+) m/z 390.1, 392.1 (M+H).

Example 341 Synthesis of 5-chloro-4-((cyclohexyloxy)methyl)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 339 Step 4 and makingnon-critical variations to replace azetidine-1-sulfonamide with methanesulfonamide, the title compound was obtained (0.005 g, 3% yield) as acolorless solid: MS (ES+) m/z 364.1, 366.1 (M+H).

Example 342 Synthesis of4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Step 1. Preparation of cyclohexenylmethanol

To a mixture of lithium aluminum hydride (9.19 g, 248 mmol) in anhydrousdiethyl ether was added a solution of methyl cyclohex-1-enecarboxylate(11.60 g, 82.80 mmol) at 0° C. over 20 minutes. The reaction mixture wasstirred at the same temperature for another 25 minutes then poured ontoice in diethyl ether (500 mL). The mixture was stirred at ambienttemperature for 16 hours and filtered the solid. The filtrate wasconcentrated in vacuo to dryness and the residue was purified by columnchromatography with ethyl acetate in hexanes (30%) to afford the titlecompound as a colorless liquid (8.76 g, 94%): ¹H NMR (300 MHz, CDCl₃) δ5.64-5.58 (m, 1H), 3.90 (s, 2H), 3.35 (d, J=6.4 Hz, 1H), 2.00-1.90 (m,4H), 1.72-1.50 (m, 4H).

Step 2. Preparation of bicyclo[4.1.0]heptan-1-ylmethanol

To a solution of diethyl zinc (1.0 M in hexanes, 15.70 mL, 15.70 mmol)in anhydrous dichloromethane (15.7 mL) was added dropwisetrifluoroacetic acid (1.79 g in 15.7 mL anhydrous dichloromethane, 15.7mmol) at 0° C. over 20 minutes. The reaction mixture was stirred at thesame temperature for 20 minutes, and then added dropwise a solution ofdiidomethane (4.20 g, 15.70 mmol) in anhydrous dichloromethane (15.7 mL)at 0° C. over 10 minutes. The reaction mixture was further stirred atthe same temperature for another 20 minutes. To this reaction mixturewas added a solution of cyclohexenylmethanol (1.07 g, 6.30 mmol) inanhydrous dichloromethane (17 mL) at 0° C. The resulting mixture waswarmed to ambient temperature and further stirred for 1 hour. Themixture was quenched with a saturated solution of ammonium chloride (50mL) and separated the organic layer. The aqueous layer was extractedwith dichloromethane (15 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated in vacuo todryness. The residue was purified by column chromatography with diethylether in hexanes (30%) to afford the title compound as colorless oil(1.00 g, 86%): ¹H NMR (300 MHz, CDCl₃) δ 3.32 (dd, J=10.9, 10.9 Hz, 2H),1.90-1.80 (m, 2H), 1.75-1.55 (m, 2H), 1.34 (br, s, 1H), 1.26-1.14 (m,2H), 0.45 (dd, J=9.3, 4.5 Hz, 1H), 0.24 (t, J=4.9 Hz, 1H).

Step 3. Preparation of tert-butyl4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate

A mixture of bicyclo[4.1.0]heptan-1-ylmethanol (0.86 g, 6.80 mmol),tert-butyl 5-chloro-2,4-difluorobenzoate (1.69 g, 6.80 mmol) and cesiumcarbonate (4.40 g, 13.7 mmol) in anhydrous dimethylsulfoxide (15 mL) washeated at 100° C. under nitrogen for 16 hours. The reaction mixture wasfiltered through a pad of diatomaceous earth and rinsed with ethylacetate (100 mL). The organic layer was washed with 1.0 M hydrochloricacid (20 mL), dried over anhydrous sodium sulfate and concentrated invacuo to dryness. The residue was purified by column chromatography witha mixture of hexanes in ethyl acetate (9:1) to afford the title compoundas a white solid (1.30 g, 54%): ¹H NMR (300 MHz, CDCl₃) 7.85 (d, J=18.4Hz, 1H), 6.54 (d, J=12.20 Hz, 1H), 3.81 (d, J=9.1 Hz, 1H), 3.68 (d,J=9.1 Hz, 1H), 1.98-1.79 (m, 4H), 1.39-1.29 (m, 3H), 1.56 (s, 9H),1.02-0.94 (min, 1H), 0.89-0.83 (m, 1H), 0.67-0.62 (m, 1H), 0.40-0.37 (m,1H); MS (ES+) m/z 377.2, 379.2 (M+23).

Step 4. Preparation of tert-butyl4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate

In a sealed tube containing tert-butyl4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate (1.30 g,3.70 mmol), cyclopropylboronic acid (0.47 g, 5.50 mmol),tricyclohexylphosphine tetrafluoroborate (0.27 g, 0.74 mmol) andpalladium acetate (0.08 g, 0.37 mmol) and potassium phosphate (3.13 g,14.8 mmol) in toluene (20 mL) and water (2.0 mL) was bubbled with anitrogen atmosphere for 10 minutes. The reaction mixture was heated to140° C. for 6 hours and cooled to ambient temperature. The solvent wasconcentrated in vacuo to dryness. The crude residue was purified columnchromatography (10% gradient ethyl acetate in hexanes) afforded thetitle compound as a colorless solid (1.00 g, 75%): ¹H NMR (300 MHz,CDCl₃) 7.37 (d, J=8.5 Hz, 1H), 6.42 (d, J=12.8 Hz, 1H), 3.61 (d, J=9.1Hz, 1H), 3.78 (d, J=9.1 Hz, 1H), 1.96-1.52 (m, 7H), 1.55 (s, 9H),0.92-0.82 (m, 4H), 0.67-0.61 (m, 4H), 0.38-0.33 (m, 1H).

Step 5. Preparation of4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid

Following the procedure as described in Example 332 Step 6 and makingnon-critical variations to replace tert-butyl4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate withtert-butyl4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate, thetitle compound was obtained as a colorless solid (0.30 g, 37%): ¹H NMR(300 MHz, CDCl₃) δ 7.37 (d, J=8.5 Hz, 1H), 6.42 (d, J=12.8 Hz, 1H), 3.61(d, J=9.1 Hz, 1H), 3.78 (d, J=9.1 Hz, 1H), 1.96-1.52 (m, 7H), 0.92-0.82(m, 4H), 0.67-0.61 (m, 4H), 0.38-0.33 (m, 1H).

Step 6. Preparation of4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide(XPC127406)

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide withcyclopropanesulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained following purification byreverse-phase HPLC as a colorless powder (0.037 g, 37%): ¹H NMR (300MHz, DMSO-d₆) δ 11.81 (br s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.87 (d,J=13.1 Hz, 1H), 3.92-3.73 (m, 2H), 3.13-3.01 (m, 1H), 2.10-1.96 (m, 1H),1.95-1.49 (m, 4H), 1.40-1.03 (m, 8H), 1.03-0.93 (m, 1H), 0.94-0.82 (m,2H), 0.77-0.59 (m, 3H), 0.41-0.32 (m, 1H); MS (ES+) m/z 408.1 (M+1)

Example 343 Synthesis of4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide with2-methoxyethanesulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-(bicyclo[4.1.0]-heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained following purification byreverse-phase HPLC as a colorless powder (0.035 g, 39%): ¹H NMR (300MHz, DMSO-d₆) δ 11.87 (br s, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.86 (d,J=13.1 Hz, 1H), 3.72 (s, 3H), 3.36-3.31 (m, 4H), 3.22-3.19 (m, 2H),2.12-1.96 (m, 1H), 1.95-1.67 (m, 3H), 1.66-1.50 (m, 1H), 1.44-1.04 (m,4H), 1.02-0.82 (m, 3H), 0.76-0.55 (m, 3H), 0.43-0.30 (m, 1H); MS (ES+)m/z 426.1 (M+1)

Example 344 Synthesis ofN-(azetidin-1-ylsulfonyl)-4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide withazetidine-1-sulfonamide and to replace4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid with4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid,the title compound was obtained following purification by reverse-phaseHPLC as a colorless powder (0.037 g, 37%): ¹H NMR (300 MHz, DMSO-d₆) δ11.60 (br, s, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.87 (d, J=13.0 Hz, 1H),4.09-3.98 (m, 4H), 3.92-3.84 (m, 1H), 3.80-3.74 (m, 1H), 2.23-1.98 (m,3H), 1.96-1.68 (m, 3H), 1.66-1.52 (m, 1H), 1.34-1.13 (m, 4H), 1.04-0.83(m, 3H), 0.75-0.60 (m, 3H), 0.41-0.33 (m, 1H); MS (ES+) m/z 423.1 (M+1)

Example 345 Synthesis of4-(adamantan-2-yl)-3-chloro-N-(methylsulfonyl)benzamide

Step 1. Preparation of tert-butyl 4-bromo-3-chlorobenzoate

To a solution of 4-bromo-3-chlorobenzoic acid (30.0 g, 127.00 mmol) inanhydrous tetrahydrofuran (500 mL) was added di-tert-butyl dicarbonate(62.60 g, 277.00 mmol) and N,N-dimethylaminopyridine (3.11 g, 25.50mmol). The mixture was stirred at ambient temperature for 18 hours andconcentrated in vacuo to half its volume. The mixture was diluted withethyl acetate (500 mL), washed with 1 M hydrochloric acid (2×500 mL),saturated aqueous sodium bicarbonate (2×500 mL), dried over anhydroussodium sulfate, filtered and concentrated to afford the title compoundas a colorless oil that was used without further purification (31.20 g,84%).

Step 2. Preparation of tert-butyl3-chloro-4-(2-hydroxyadamantan-2-yl)benzoate

To a cold (−40° C.) solution of 2-adamantanone (1.50 g, 10.00 mmol) andtert-butyl 4-bromo-3-chlorobenzoate (2.45 g, 10.00 mmol) in anhydroustetrahydrofuran (120 mL) was added isopropylmagnesium chloride lithiumchloride complex (1.3 M solution in tetrahydrofuran, 10 mL, 13 mmol).The reaction mixture was warm to ambient temperature over 2 hours andheated to reflux for 1 hour. After cooling to ambient temperature, themixture was quenched with saturated aqueous ammonium chloride (10 mL),diluted with ethyl acetate (200 mL), washed with saturated aqueousammonium chloride

(2×100 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to dryness. The residue was purified by columnchromatography with a gradient of 0-30% ethyl acetate in hexanes toafford the title compound as a colorless gum (0.58 g, 16%): ¹H NMR (300MHz, CDCl₃) δ 7.95 (d, J=1.4 Hz, 1H), 7.84 (dd, J=1.3, 8.3 Hz, 1H), 7.63(d, J=8.4 Hz, 1H), 2.90 (br s, 3H), 2.51-2.47 (m, 2H), 1.87-1.65 (m,10H), 1.59 (s, 9H); MS (ES−) m/z 363.2, 365.1 (M+1).

Step 3. Preparation of 4-(adamantan-2-yl)-3-chlorobenzoic acid

To a solution of tert-butyl 3-chloro-4-(2-hydroxyadamantan-2-yl)benzoate(0.581 g, 1.60 mmol) in dichloromethane (50 mL) was added triethylsilane(5 mL) and trifluoroacetic acid (5 mL). The reaction mixture was stirredat ambient temperature for 20 hours and the reaction solution wasconcentrated in vacuo to dryness. The residue was triturated withhexanes (15 mL) to afford the title compound (0.27 g, 57%) as acolorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.06 (d, J=1.6 Hz, 1H), 7.94(dd, J=1.6, 8.2 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 3.33 (s, 1H), 2.33 (brs, 2H), 1.98-1.92 (m, 8H), 1.78 (s, 2H), 1.70-1.66 (m, 2H) (OH notobserved); MS (ES−) m/z 289.3, 291.3 (M−1).

Step 4. Preparation of4-((adamantan-2-yl)-3-chloro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-(adamantan-2-yl)-3-chlorobenzoic acid, the title compound wasobtained following trituration with hexanes (10 mL) as a colorless solid(0.11 g, 65%): ¹H NMR (300 MHz, CDCl₃) δ 8.81 (s, 1H), 7.86-7.85 (m,1H), 7.73-7.66 (m, 2H), 3.43 (s, 3H), 3.31 (s, 1H), 2.31 (s, 2H),2.03-1.90 (m, 8H), 1.78 (s, 2H), 1.70-1.65 (m, 2H); MS (ES−) m/z 368.2,366.2 (M−1).

Example 346 Synthesis of4-(adamantan-2-yl)-3-chloro-N-(N-methylsulfamoyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide with methylsulfamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-(adamantan-2-yl)-3-chlorobenzoic acid, the title compound wasobtained following trituration with hexanes as a colorless solid (0.11g, 66%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.81 (s, 1H) 7.98-7.97 (m, 1H),7.88-7.85 (m, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.64-7.60 (m, 1H), 3.22 (s,1H), 2.50 (d, J=4.4 Hz, 3H), 2.23 (s, 2H), 1.95-1.85 (m, 8H), 1.72 (s,2H), 1.63-1.59 (m, 2H); MS (ES−) m/z 381.2, 383.2 (M−1).

Example 347 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-4-((7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzamide

Step 1. Preparation of 1-((cyclohexenylmethoxy)methyl)-4-methoxybenzene

To a mixture of cyclohexenylmethanol (2.50 g, 22.3 mmol) inN,N-dimethylformamide (40 mL) and sodium hydride (60% dispersion inmineral oil, 0.89 g, 22.3 mmol) was added in portions at 0° C. Thereaction mixture was stirred for 0.5 hour, then added1-(chloromethyl)-4-methoxybenzene (3.49 g, 22.3 mmol). The reactionmixture was stirred for another 0.5 hour and quenched with slow additionof water (50 mL). The organic layer was extracted with ethyl acetate (80mL) and concentrated in vacuo to dryness. The residue was purified bycolumn chromatography with ethyl acetate in hexanes (10%) to afford thetitle compound as a colorless liquid (3.50 g, 68%).

Step 2. Preparation of 7,7-difluoro-1-((4-methoxybenzyloxy)-methyl)bicyclo[4.1.0]heptane

To a microwave 5 mL vial was added 1-((cyclohexenylmethoxy)-methyl)-4-methoxybenzene (0.46 g, 2.00 mmol),trimethyl(2,2,2-trifluoroethyl)silane (0.57 g, 4.00 mmol) and sodiumiodide (0.66 g, 4.40 mmol) in anhydrous tetrahydrofuran (1.0 mL). Thevial was degassed with nitrogen and sealed. The reaction mixture washeated in the microwave reactor at 115° C. for 1 hour. The reaction vialwas cooled and the TLC showed presence of starting material. To thereaction vial was added trimethyl(2,2,2-trifluoroethyl)silane (0.5 mL)and continued heating in the microwave at the same temperature foranother 1 hour. The reaction was filtered, washed with ethyl acetate (10ml). The filtrate was concentrated in vacuo to dryness. The residue waspurified by column chromatography with ethyl acetate in hexanes (20%) toafford the title compound as colourless liquid (0.45 g, 80%).

Step 3. Preparation of (7,7-difluorobicyclo[4.1.0]heptan-1-yl)methanol

To a solution of 7,7-difluoro-1-((4-methoxybenzyloxy)methyl)-bicyclo[4.1.0]heptane (2.50 g, 8.90 mmol) in dichloromethane (20 mL) andwater (3.0 mL) was added DDQ (3.00 g, 13.3 mmol) at 0° C. The reactionmixture was stirred at the same temperature for 3 hour. Water (1.5 mL)was added followed by sodium sulfate (10 g). The resulting suspensionwas filtered through a short pad of silica gel column with ethyl acetatein hexanes (30%) to afford the title compound as a colorless liquid(0.90 g, 62%).

Step 4. Preparation of tert-butyl5-chloro-4-((7,7-difluorobicyclo[4.1.0]heptan-1-yl)-methoxy)-2-fluorobenzoate

Following the procedure as described in Example 342 Step 3 and makingvariations as required to replace bicyclo[4.1.0]heptan-1-ylmethanol with(7,7-difluorobicyclo[4.1.0]heptan-1-yl)methanol, the title compound wasobtained as a colorless gum (1.90 g, 53%): ¹H NMR (300 MHz, CDCl₃) δ7.89 (d, J=7.6 Hz, 1H), 6.59 (d, J=11.9 Hz, 1H), 4.05-3.88 (m, 2H),2.00-1.67 (m, 4H), 1.58 (s, 9H), 1.44-1.29 (m, 5H); MS (ES+) m/z 341.1,343.1 (M+1).

Step 5. Preparation of5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoicacid

Following the procedure as described in Example 332 Step 6 and makingnon-critical variations to replace tert-butyl4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate withtert-butyl5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]-heptan-1-yl)methoxy)-2-fluorobenzoate,the title compound was obtained (0.48 g, 80%) as a colorless solid: ¹HNMR (300 MHz, CDCl₃) δ 7.53 (d, J=8.4 Hz, 1H), 6.51 (d, J=12.6 Hz, 1H),4.00-3.90 (m, 2H), 1.97-1.71 (m, 5H), 1.47-1.22 (m, 5H), 0.95-0.86 (m,2H), 0.69-0.61 (m, 2H).

Step 6. Preparation ofN-(azetidin-1-ylsulfonyl)-5-chloro-4-((7,7-difluorobicyclo[4.1.0]-heptan-1-yl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide withazetidine-1-sulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained following purification byreverse-phase HPLC as a colorless powder (0.037 g, 37%): ¹H NMR (300MHz, DMSO-d₆) δ 11.86 (br s, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.25 (d,J=12.2 Hz, 1H), 4.28-4.20 (m, 1H), 4.14-3.97 (m, 4H), 2.25-2.08 (m, 2H),1.98-1.52 (m, 6H), 1.39-1.16 (m, 4H); MS (ES+) m/z 459.1 (M+1).

Example 348 Synthesis of5-chloro-N-(cyclopropylsulfonyl)-4-((7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide withcyclopropanesulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained following purification byreverse-phase HPLC as a colorless powder (0.045 g, 74%): ¹H NMR (300MHz, CDCl₃) δ 12.08 (br, s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.25 (d, J=12.4Hz, 1H), 4.31-4.03 (m, 2H), 3.14-2.97 (m, 1H), 1.99-1.57 (m, 5H),1.38-1.18 (m, 4H), 1.18-1.06 (m, 4H); MS (ES+) m/z 444.1 (M+1).

Example 349 Synthesis of5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluoro-N-((2-methoxyethyl)sulfonyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide with2-methoxyethanesulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained following purification byreverse-phase HPLC as a colorless powder (0.045 g, 74%): ¹H NMR (300MHz, DMSO-d₆) δ 11.92 (br s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.94 (d,J=12.8 Hz, 1H), 4.23-3.92 (m, 2H), 3.72 (s, 3H), 3.39-3.28 (m, 2H),3.23-3.18 (m, 2H), 2.08-1.58 (m, 6H), 1.38-1.16 (m, 4H), 0.96-0.84 (m,2H), 0.74-0.64 (m, 2H); MS (ES+) m/z 463.0 (M+1)

Example 350 Synthesis of5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained following purification byreverse-phase HPLC as a colorless powder (0.045 g, 48%): ¹H NMR (300MHz, DMSO-d₆) δ 11.93 (br s, 1H), 7.17 (d, J=8.3 Hz, 1H), 6.95 (d,J=12.9 Hz, 1H), 4.21-3.96 (m, 2H), 3.34 (s, 3H), 2.09-1.57 (m, 6H),1.37-1.18 (m, 4H), 0.95-0.85 (m, 2H), 0.74-0.67 (m, 2H); MS (ES+) m/z418.1 (M+1).

Example 351 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-fluorocyclohexyl)methoxy)benzamide

Step 1. Preparation of tert-butyl5-chloro-2-fluoro-4-((1-fluorocyclohexyl)-methoxy)-benzoate

Following the procedure as described in Example 342 Step 3 and makingvariations as required to replace bicyclo[4.1.0]heptan-1-ylmethanol with(1-fluorocyclohexyl)methanol, the title compound was obtained as acolorless gum (1.7 g, 83%): ¹H NMR (300 MHz, CDCl₃) δ 7.86 (d, J=7.7 Hz,1H), 6.63 (d, J=12.0 Hz, 1H), 3.98 (d, J=17.6 Hz, 2H), 2.06-1.88 (m,2H), 1.74-1.58 (m, 6H), 1.55 (s, 9H), 1.37-1.21 (m, 2H).

Step 2. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((1-fluorocyclohexyl)-methoxy)-benzoate

Following the procedure as described in Example 342 Step 4 and makingvariations as required to replace tert-butyl4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate withtert-butyl 5-chloro-2-fluoro-4-((1-fluorocyclohexyl)methoxy)benzoate,the title compound was obtained as a colorless gum (1.60 g, 90%): ¹H NMR(300 MHz, CDCl₃) δ 7.38 (d, J=8.4 Hz, 1H), 6.49 (d, J=12.5 Hz, 1H), 3.93(d, J=17.8 Hz, 2H), 2.04-1.87 (m, 4H), 1.73-1.55 (m, 6H), 1.54 (s, 9H),1.36-1.20 (m, 3H), 0.91-0.80 (m, 2H), 0.65-0.57 (m, 2H).

Step 3. Preparation of5-cyclopropyl-2-fluoro-4-((1-fluorocyclohexyl)-methoxy)benzoic acid

Following the procedure as described in Example 332 Step 6 and makingnon-critical variations to replace tert-butyl4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate withtert-butyl5-cyclopropyl-2-fluoro-4-((1-fluorocyclohexyl)-methoxy)benzoate, thetitle compound was obtained as a colorless solid (0.48 g, 80%): ¹H NMR(300 MHz, CDCl₃) δ 7.52 (d, J=8.4 Hz, 1H), 6.57 (d, J=12.5 Hz, 1H), 3.98(d, J=17.9 Hz, 2H), 2.10-1.89 (m, 2H), 1.76-1.51 (m, 6H), 1.39-1.21 (m,1H), 0.95-0.86 (m, 2H), 0.69-0.59 (m, 2H).

Step 4. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-fluorocyclohexyl)methoxy)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methane sulfonamide withazetidine-1-sulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-cyclopropyl-2-fluoro-4-((1-fluorocyclohexyl)methoxy)benzoic acid,the title compound was obtained following purification by reverse-phaseHPLC as a colorless powder (0.037 g, 37%): ¹H NMR (300 MHz, DMSO-d₆)11.64 (br s, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 4.16(d, J=8.3 Hz, 2H), 4.05 (dd, J=8.3, 4H), 2.25-1.82 (m, 5H), 1.78-1.45(m, 7H), 1.41-1.21 (m, 1H), 0.96-0.86 (m, 2H), 0.75-0.63 (m, 2H); MS(ES+) m/z 429.1 (M+1)

Example 352 Synthesis ofN-(Azetidin-1-ylsulfonyl)-4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzamide

Step 1. Preparation of tert-butyl5-chloro-4-(cyclopentylmethoxy)-2-fluorobenzoate

Following the procedure as described in Example 342 step 3 and makingvariations as required to replace bicyclo[4.1.0]heptan-1-ylmethanol withcyclopentylmethanol, the title compound was obtained as a colorless gum(3.0 g, 46%): ¹H NMR (300 MHz, CDCl₃) 7.85 (d, J=7.7 Hz, 1H), 6.61 (d,J=7.7 Hz, 1H), 3.91-3.87 (m, 2H), 1.93-1.76 (m, 2H), 1.71-1.58 (m, 5H),1.56 (s, 9H), 1.43-1.25 (m, 2H).

Step 2. Preparation of4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid

Following the procedure as described in Example 332 Step 6 and makingnon-critical variations to replace tert-butyl4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate withtert-butyl 4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzoate, thetitle compound was obtained as a colorless solid (3.0 g, 46%): ¹H NMR(300 MHz, CDCl₃) δ 7.27 (d, J=7.72 Hz, 1H), 6.85 (d, J=7.72 Hz, 1H),3.92 (d, J=6.78 Hz, 2H), 2.38-2.22 (m, 1H), 2.05-1.89 (m, 1H), 1.83-1.67(m, 2H), 1.64-1.44 (m, 4H), 1.41-1.26 (m, 2H), 0.89-0.79 (m, 2H),0.60-0.52 (m, 2H).

Step 3. Preparation ofN-(azetidin-1-ylsulfonyl)-4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide withazetidine-1-sulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid, thetitle compound was obtained following purification by reverse-phase HPLCas a colorless powder (0.037 g, 37%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.60(br s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.96 (d, J=13.0 Hz, 1H), 4.15-3.89(m, 6H), 2.42-2.28 (m, 1H), 2.23-2.10 (m, 2H), 2.08-1.96 (m, 1H),1.87-1.71 (m, 2H), 1.70-1.46 (m, 4H), 1.45-1.28 (m, 2H), 0.95-0.82 (m,2H), 0.73-0.64 (m, 2H); MS (ES+) m/z 397.2 (M+1)

Example 353/354 Synthesis of (1s,3R,4r,5S,7s)-methyl4-(2-chloro-5-fluoro-4-((methyl-sulfonyl)carbamoyl)-phenoxy)adamantane-1-carboxylate

And (1s,3R,4s,5S,7s)-methyl4-(2-chloro-5-fluoro-4-((methylsulfonyl)-carbamoyl)-phenoxy)adamantane-1-carboxylate

Step 1. Preparation of (1s,3R,5S,7s)-methyl4-oxoadamantane-1-carboxylate

To a solution of (1s,3R,5S,7s)-4-oxoadamantane-1-carboxylic acid (10.00g, 51.50 mmol) in methanol (100 mL) was added thionyl chloride (5.0 mL,69.00 mmol). The mixture was heated to reflux for 4 hours, cooled toambient temperature and concentrated in vacuo to dryness. The residuewas dissolved in ethyl acetate (200 mL), washed with saturated aqueoussodium bicarbonate (2×150 mL), brine (150 mL), dried over anhydroussodium sulfate, filtered and concentrated in vacuo to afford the titlecompound as a colorless oil (8.60 g, 80%): ¹H NMR (300 MHz, CDCl₃) δ3.66 (s, 3H), 2.57 (br s, 2H), 2.18-2.17 (m, 5H), 2.10-1.99 (m, 6H).

Step 2. Preparation of (1s,3R,5S,7s)-methyl4-hydroxyadamantane-1-carboxylate

To a cold (0° C.) solution of (1s,3R,5S,7s)-methyl4-oxoadamantane-1-carboxylate (4.50 g, 22.00 mmol) in methanol (50 mL)was added sodium borohydride (0.99 g, 26.00 mmol). The mixture wasstirred for 2 hours and quenched with saturated aqueous ammoniumchloride (10 mL). The mixture was diluted with ethyl acetate (200 mL),washed with saturated aqueous ammonium chloride (2×150 mL) and brine(150 mL), dried over anhydrous sodium sulfate, filtered and concentratedto give the title compound as a colorless oil (2.51 g, 55%): ¹H NMR (300MHz, CDCl₃) δ 3.88 (br s, 0.5H), 3.82 (br s, 0.5H), 3.65 (s, 1.5H), 3.64(s, 1.5H), 2.25-2.21 (m, 1H), 2.10-1.77 (m, 10.5H), 1.68-1.63 (m, 1.5H),1.48-1.44 (m, 1H); MS (ES−) m/z 211.2 (M+1).

Step 3. Preparation of (1s,3R,5S,7s)-methyl4-(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)adamantane-1-carboxylate

Following the procedure as described in Example 332 Step 4 and makingnon-critical variations to replace(1r,3r,5r,7r)-2-(hydroxymethyl)adamantane-2-carbonitrile with(1s,3R,5S,7s)-methyl 4-hydroxyadamantane-1-carboxylate, the titlecompound was obtained following purification by column chromatographywith a 0-30% gradient of ethyl acetate in hexanes as a colorless oil anda ˜1:1 mix of diastereomers (0.55 g, 48%): ¹H NMR (300 MHz, CDCl₃) δ7.87 (d, J=7.8 Hz, 0.5H), 7.86 (d, J=7.8 Hz, 0.5H), 6.61 (d, J=12.3 Hz,0.5H), 6.60 (d, J=12.3 Hz, 0.5H), 4.47 (br s, 0.5H), 4.41 (br s, 0.5H),3.66 (s, 1.5H), 3.65 (s, 1.5H), 2.32-2.15 (m, 4H), 2.07-1.86 (m, 7H),1.76-1.69 (m, 2H), 1.55 (s, 9H); MS (ES−) m/z 439.2, 441.2 (M+1).

Step 4. Preparation of5-chloro-2-fluoro-4-(((1R,3S,5s,7s)-5-(methoxycarbonyl)-adamantan-2-yl)oxy)benzoicacid

Following the procedure as described in Example 332 Step 6 and makingnon-critical variations to replace tert-butyl4-(((r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoatewith (1s,3R,5S,7s)-methyl4-(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)adamantane-1-carboxylate,the title compound was obtained as a colorless solid as a ˜1:1 mix ofdiastereomers (0.52 g, quant.): ¹H NMR (300 MHz, CDCl₃) δ 8.04-8.01 (m,1H), 7.52 (br s, 1H), 6.68-6.63 (m, 1H), 4.51 (br s, 0.5H), 4.45 (br s,0.5H), 3.68 (s, 1.5H), 3.66 (s, 1.5H), 2.32-2.16 (m, 4H), 2.08-1.74 (m,8H), 1.55-1.51 (m, 1H); MS (ES−) m/z 383.0, 384.9 (M+1).

Step 5. Preparation of (1s,3R,4r,5S,7s)-methyl4-(2-chloro-5-fluoro-4-((methylsulfonyl)-carbamoyl)phenoxy)adamantane-1-carboxylateand (1s,3R,4s,5S,7s)-methyl 4-(2-chloro-5-fluoro-4-((methylsulfonyl)-carbamoyl)phenoxy)adamantane-1-carboxylate

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid with5-chloro-2-fluoro-4-(((1R,3S,5s,7s)-5-(methoxycarbonyl)adamantan-2-yl)oxy)benzoicacid, the title compounds were obtained following purification byreverse-phase HPLC as pure and separated materials. Data for the firstfraction, (1s,3R,4r,5S,7s)-methyl4-(2-chloro-5-fluoro-4-((methylsulfonyl)-carbamoyl)phenoxy)adamantane-1-carboxylate:a colorless solid (not weighed): ¹H NMR (300 MHz, DMSO-d₆) δ 12.04 (brs, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.34 (d, J=12.7 Hz, 1H), 4.74 (br s,1H), 3.55 (s, 3H), 3.31 (s, 3H), 2.16-2.08 (m, 4H), 1.93 (br s, 1H),1.81-1.72 (m, 6H), 1.64 (br s, 1H), 1.60 (br s, 1H); MS (ES−) m/z458.12, 460.10 (M−1). Data for the second fraction,(1s,3R,4s,5S,7s)-methyl 4-(2-chloro-5-fluoro-4-((methylsulfonyl)-carbamoyl)phenoxy)adamantane-1-carboxylate: a colorless solid (notweighed): ¹H NMR (300 MHz, DMSO-d₆) δ 12.04 (br s, 1H), 7.75 (d, J=7.6Hz, 1H), 7.35 (d, J=12.7 Hz, 1H), 4.81 (br s, 1H), 3.58 (s, 3H), 3.31(s, 3H), 2.13 (br s, 3H), 2.01-1.74 (m, 8H), 1.45-1.43 (m, 2H); MS (ES−)m/z 458.1, 460.1 (M−1).

Examples 355/356 Synthesis of (1s,3R,4r,5S,7s)-methyl4-(2-chloro-5-fluoro-4-((N-methylsulfamoyl)-carbamoyl)phenoxy)adamantane-1-carboxylate

And (1s,3R,4s,5S,7s)-methyl4-(2-chloro-5-fluoro-4-((N-methylsulfamoyl)carbamoyl)-phenoxy)adamantane-1-carboxylate

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide with methylsulfamide and to replace4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid with5-chloro-2-fluoro-4-(((1R,3S,5s,7s)-5-(methoxycarbonyl)adamantan-2-yl)oxy)benzoicacid, the title compounds were obtained following purification byreverse-phase HPLC as pure and separated materials. Data for the firstfraction, (1s,3R,4r,5S,7s)-methyl4-(2-chloro-5-fluoro-4-((N-methylsulfamoyl)carbamoyl)-phenoxy)adamantane-1-carboxylate:a colorless solid (not weighed): ¹H NMR (300 MHz, DMSO-d₆) δ 11.64 (s,1H), 7.70 (d, J=7.5 Hz, 1H), 7.66-7.61 (m, 1H), 7.32 (d, J=12.6 Hz, 1H),4.73 (br s, 1H), 3.55 (s, 3H), 2.52 (d, J=4.7 Hz, 3H), 2.16-2.08 (m,4H), 1.93 (br s, 1H), 1.81-1.72 (m, 6H), 1.64 (br s, 1H), 1.60 (br s,1H); MS (ES−) m/z 474.99, 476.98 (M−1). Data for the second fraction,(1s,3R,4s,5S,7s)-methyl 4-(2-chloro-5-fluoro-4-((N-methylsulfamoyl)-carbamoyl)phenoxy)adamantane-1-carboxylate: a colorless solid (notweighed): ¹H NMR (300 MHz, DMSO-d₆) δ 11.63 (s, 1H), 7.71-7.63 (m, 2H),7.34 (d, J=12.5 Hz, 1H), 4.80 (br s, 1H), 3.58 (s, 3H), 2.52 (d, J=4.7Hz, 3H), 2.13 (br s, 2H), 2.01-1.74 (m, 9H), 1.47 (br s, 1H), 1.43 (brs, 1H); MS (ES−) m/z 474.9, 576.9 (M−1).

Example 357 Synthesis of5-chloro-N-(cyclopropylsulfonyl)-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzamide

Step 1. Preparation of 1,4-dioxaspiro[4.5]decan-8-ol

A solution of 1,4-dioxaspiro[4.5]decan-8-one (20.40 g, 130.60 mmol) inanhydrous methanol (200 mL) at 0° C., under nitrogen, was treated withsodium borohydride (2.50 g, 65.30 mmol), portion wise. The resultingmixture was stirred for 24 hours and concentrated in vacuo to dryness.The residue was diluted with ethyl acetate (300 mL), washed with 1 Mhydrochloric acid (3×100 mL), brine (3×100 mL), dried over anhydroussodium sulfate and concentrated in vacuo to afford the title compound asa colorless oil (11.2 g, 51%): ¹H NMR (300 MHz, CDCl₃) δ 3.91-3.87 (m,4H), 3.79-3.70 (m, 1H), 1.92 (br s, 1H), 1.89-1.71 (m, 4H), 1.67-1.47(m, 4H); MS (ES+) m/z 140.9 (M-OH).

Step 2. Preparation of4-(1,4-dioxaspiro[4.5]decan-8-yloxy)-5-chloro-2-fluorobenzoic acid

To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (12.90 g, 81.50 mmol) indimethylsulfoxide (800 mL) was added potassium tert-butoxide (21.00 g,187.00 mmol). The reaction mixture was stirred at ambient temperaturefor 15 minutes under nitrogen. To this mixture was added5-chloro-2,4-difluorobenzoic acid (15.70 g, 81.70 mmol). The mixture wasstirred at ambient temperature for 3 days, after which it was split intotwo equal portions. Each portion was diluted with ethyl acetate (700mL), washed with 1 M hydrochloric acid (700 mL), a 1:1 mixture of 1 Mhydrochloric acid and brine (700 mL), and brine (700 mL). The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo to dryness. The residue was purified by column chromatographywith a gradient of a solution of 0.2% acetic acid in ethyl acetate andhexanes from 0-50%, to afford the title compound as a light yellow solid(5.66 g, 21%): ¹H NMR (300 MHz, CDCl₃) δ 9.24 (br s, 1H), 8.01 (d, J=7.7Hz, 1H), 6.69 (d, J=12.4 Hz, 1H), 4.54-4.51 (m, 1H), 3.97-3.95 (m, 4H),2.06-1.93 (m, 4H), 1.81-1.74 (m, 1H), 1.70-1.51 (m, 3H); MS (ES−) m/z329.1, 331.1 (M−1).

Step 3. Preparation of 5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoicacid

To a solution of4-(1,4-dioxaspiro[4.5]decan-8-yloxy)-5-chloro-2-fluorobenzoic acid (2.95g, 8.92 mmol) in acetone (100 mL) was added 3 M hydrochloric acid (80mL). The solution was heated to reflux for 17 hours and cooled toambient temperature. The mixture was diluted with brine (200 mL) andextracted with ethyl acetate (3×150 mL). The combined organic layerswere dried over anhydrous sodium sulfate, filtered, and concentrated invacuo to dryness. The residue was purified by column chromatography witha gradient of a solution of 0.2% acetic acid in ethyl acetate andhexanes from 0-50% to afford the title compound as a colorless solid(1.14 g, 45%): ¹H NMR (300 MHz, CDCl₃) δ 8.07 (d, J=7.6 Hz, 1H), 6.77(d, J=11.9 Hz, 1H), 4.82 (br s, 1H), 2.81-2.70 (m, 2H), 2.41-2.35 (m,4H), 2.15-2.03 (m, 2H) (OH not observed); MS (ES−) m/z 285.1, 287.1(M−1).

Step 4. Preparation of methyl5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoate

To a solution of 5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoic acid(1.14 g, 3.98 mmol) in anhydrous tetrahydrofuran (50 mL) was added1,1′-carbonyldiimidazole (1.71 g, 10.50 mmol). The solution was heatedto reflux under a nitrogen atmosphere for 1 hours and cooled to ambienttemperature. To the solution was added anhydrous methanol (0.49 mL,12.00 mmol) and 1,8-diazabicycloundec-7-ene (1.8 mL, 12.00 mmol). Thesolution was stirred at ambient temperature for 4 h, then diluted withethyl acetate (150 mL) and washed with 1 M hydrochloric acid (2×150 mL),brine (150 mL), dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated in vacuo to afford the title compound asan off-white solid (1.05 g, 87%): ¹H NMR (300 MHz, CDCl₃) δ 7.99 (d,J=7.6 Hz, 1H), 6.74 (d, J=12.0 Hz, 1H), 4.79 (br s, 1H), 3.89 (s, 3H),2.79-2.68 (m, 2H), 2.39-2.31 (m, 4H), 2.13-2.02 (m, 2H); MS (ES+) m/z300.9 (M+1).

Step 5. Preparation of methyl5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoate

To a cold (0° C.) solution of diethylaminosulfur trifluoride (1.2 mL,9.30 mmol) in anhydrous 1,2-dichloroethane (15 mL) was added a solutionof methyl 5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoate (1.02 g,3.40 mmol) in 1,2-dichloroethane (5 mL) dropwise over 5 minutes. Themixture was allowed to warm to ambient temperature and stirred under anitrogen atmosphere for 4 hours. The mixture was quenched with saturatedaqueous ammonium chloride (5 mL), diluted with saturated aqueousammonium chloride (75 mL) and water (25 mL). The mixture was extractedwith dichloromethane (2×150 mL) and the combined organic layers weredried over anhydrous magnesium sulfate, filtered and concentrated invacuo to dryness. The residue was purified by column chromatography witha gradient of ethyl acetate in hexanes from 0-35% to afford the titlecompound as a colorless solid (0.70 g, 64%): ¹H NMR (300 MHz, CDCl₃) δ7.97 (d, J=7.6 Hz, 1H), 6.67 (d, J=12.0 Hz, 1H), 4.60 (br s, 1H), 3.88(s, 3H), 2.50-1.88 (m, 8H); ¹⁹F NMR (282 MHz, CDCl₃) δ −92.3 (d, J=234Hz, 1F), −102.6 (d, J=237 Hz, 1F), −107.0 (s, 1F); MS (ES+) m/z 322.9,324.9 (M+1).

Step 6. Preparation of5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acid

To a solution of methyl5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoate (0.314 g,0.973 mmol) in tetrahydrofuran (15 mL) and water (10 mL) was addedlithium hydroxide (0.148 g, 6.18 mmol). The mixture was heated to refluxfor 1.5 hours, cooled to ambient temperature. The reaction was dilutedwith 1 M hydrochloric acid (150 mL) and extracted with ethyl acetate(2×100 mL). The combined organic layers were dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to dryness. Theresidue was purified by column chromatography, with a gradient of asolution of 0.2% acetic acid in ethyl acetate and hexanes from 0-50% toafford the title compound as a colorless solid (0.25 g, 83%): ¹H NMR(300 MHz, CDCl₃) 8.05 (d, J=7.6 Hz, 1H), 6.70 (d, J=12.1 Hz, 1H), 4.63(br s, 1H), 2.52-1.90 (m, 8H); ¹⁹F NMR (282 MHz, CDCl₃) δ −92.3 (d,J=238 Hz, 1F), −102.6 (d, J=238 Hz, 1F), −105.3 (s, 1F); MS (ES−) m/z307.2, 309.2 (M−1).

Step 7. Preparation of5-chloro-N-(cyclopropylsulfonyl)-4-((4,4-difluorocyclohexyl)-oxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide withcyclopropanesulfonamide and to replace4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid with 5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acidand methanol with cyclopropyl sulfonamide, the title compound wasobtained as a colorless solid (0.047 g, 31%): ¹H NMR (300 MHz, DMSO-d₆)δ 12.02 (br s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.37 (d, J=12.6 Hz, 1H),4.85 (br s, 1H), 3.07-2.98 (m, 1H), 2.07-1.87 (m, 8H), 1.09-1.05 (m,4H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −92.3 (d, J=231 Hz, 1F), −98.5 (d,J=231 Hz, 1F), −109.9 (s, 1F); MS (ES−) m/z 410.0, 412.0 (M−1).

Example 358 Synthesis of5-cyclopropyl-4-((3,3-dimethylcyclohexyl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of tert-butyl5-chloro-4-((3,3-dimethylcyclohexyl)oxy)-2-fluorobenzoate

Following the procedure as described in Example 342 Step 3 and makingvariations as required to replace bicyclo[4.1.0]heptan-1-ylmethanol with3,3-dimethylcyclohexanol, the title compound was obtained as a colorlessgum (1.33 g, 48%): MS (ES+) m/z 357.04 (M+1).

Step 2. Preparation of tert-butyl5-cyclopropyl-4-((3,3-dimethylcyclohexyl)oxy)-2-fluorobenzoate

Following the procedure as described in Example 342 Step 4 and makingvariations as required to replace tert-butyl4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate withtert-butyl 5-chloro-4-((3,3-dimethyl- cyclohexyl)oxy)-2-fluorobenzoate,the title compound was obtained as an orange oil (1.29 g, 82%): MS (ES+)m/z 385.1 (M+23).

Step 3. Preparation of5-cyclopropyl-4-((3,3-dimethylcyclohexyl)oxy)-2-fluorobenzoic acid

Following the procedure as described in Example 332 Step 6 and makingnon-critical variations to replace tert-butyl4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate withtert-butyl5-cyclopropyl-4-((3,3-dimethylcyclohexyl)oxy)-2-fluorobenzoate, thetitle compound was obtained as a beige solid (0.87 g, 80%): MS (ES+) m/z307.10 (M+1).

Step 4. Preparation of5-cyclopropyl-4-((3,3-dimethylcyclohexyl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-cyclopropyl-4-((3,-dimethylcyclohexyl)oxy)-2-fluorobenzoic acid,the title compound was obtained as a white solid (0.027 g, 13%): ¹H NMR(300 MHz, DMSO-d₆) δ11.86 (s, 1H), 7.11 (d, J=8.5 Hz, 1H), 7.02 (d,J=13.3 Hz, 1H), 4.67-4.57 (m, 1H), 2.74-2.54 (m, 2H), 2.45-2.25 (m, 1H),2.05-1.97 (m, 2H), 1.77-1.70 (m, 1H), 1.65-1.55 (m, 2H), 1.38-1.23 (m,4H), 0.98 (s, 3H), 0.97 (s, 3H), 0.90-0.84 (m, 2H), 0.69-0.64 (m, 2H);MS (ES+) m/z 384.1 (M+1).

Example 359 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((3,3-dimethylcyclohexyl)oxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methane sulfonamide withazetidine-1-sulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-cyclopropyl-4-((3,3-dimethylcyclohexyl)oxy)-2-fluorobenzoic acid,the title compound was obtained as a white solid (0.035 g, 15%): ¹H NMR(300 MHz, DMSO-d₆) δ11.58 (s, 1H), 7.11 (d, J=8.5 Hz, 1H), 7.03 (d,J=13.3 Hz, 1H), 4.67-4.58 (m, 1H), 4.04 (t, J=7.7 Hz, 4H), 2.21-2.11 (m,2H), 2.06-1.96 (m, 2H), 1.76-1.70 (m, 1H), 1.65-1.53 (m, 2H), 1.38-1.14(m, 4H), 0.98 (s, 3H), 0.97 (s, 3H), 0.90-0.84 (m, 2H), 0.69-0.64 (m,2H); MS (ES+) m/z 425.1 (M+1).

Example 360 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((3,3-dimethyl-cyclohexyl)oxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methane sulfonamide with cyclopropanesulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-cyclopropyl-4-((3,3-dimethylcyclohexyl)oxy)-2-fluorobenzoic acid,the title compound was obtained as a white solid (0.07 g, 31%): ¹H NMR(300 MHz, DMSO-d₆) δ11.79 (s, 1H), 7.10 (d, J=8.5 Hz, 1H), 7.03 (d,J=13.3 Hz, 1H), 4.67-4.58 (m, 1H), 3.11-3.03 (m, 1H), 2.06-1.95 (m, 2H),1.76-1.70 (m, 1H), 1.65-1.54 (m, 2H), 1.37-1.17 (m, 4H), 1.13-1.08 (m,4H), 0.98 (s, 3H), 0.97 (s, 3H), 0.90-0.84 (m, 2H), 0.68-0.63 (m, 2H);MS (ES+) m/z 410.0 (M+1).

Example 361 Synthesis of4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of methyl bicyclo[4.1.0]heptane-3-carboxylate

To a solution of diethyl zinc (1.0 M in hexanes, 35 mL, 35.00 mmol) inanhydrous dichloromethane (34 mL) was added trifluoroacetic acid (3.99g, 35.0 mmol) in 17.2 mL anhydrous dichloromethane at 0° C. The reactionmixture was stirred at the same temperature for 1 hour, and then added asolution of diidomethane (9.37 g, 35.00 mmol) in anhydrousdichloromethane (17 mL) at 0° C. The reaction mixture was furtherstirred at the same temperature for another 1 hour. To this mixture wasadded a solution of methyl cyclohex-3-enecarboxylate (2.45 g, 17.50mmol) in anhydrous dichloromethane 17 mL) at 0° C. The resulting mixturewas warmed to ambient temperature and further stirred for 4 hours. Themixture was quenched with a saturated solution of ammonium chloride (50mL) and separated the organic layer. The aqueous layer was extractedwith dichloromethane (15 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated in vacuo todryness. The residue was purified by column chromatography with ethylacetate in hexanes (30%) to afford the title compound as yellow oil(2.56 g, 95%): ¹H NMR (300 MHz, CDCl₃) δ 3.64 (s, 3H), 2.31-1.92 (m,3H), 1.84-1.65 (m, 2H), 1.54 (t, J=12.9 Hz, 1H), 1.19-1.04 (m, 1H),0.93-0.86 (m, 2H), 0.63-0.55 (m, 1H), 0.05-0.00 (m, 1H).

Step 2. Preparation of bicyclo[4.1.0]heptan-3-ylmethanol

To a mixture of lithium aluminum hydride (0.74 g, 19.50 mmol) inanhydrous diethyl ether (11 mL) was added a solution of methylbicyclo[4.1.0]heptane-3-carboxylate (1.00 g, 6.50 mmol) in anhydrousdiethyl ether (4.6 mL) at 0° C. The resulting mixture stirred at 0° C.for 0.5 hour. The mixture was slowly quenched with water (1 mL) at 0° C.and warmed to ambient temperature. The mixture was filtered throughdiatomaceous earth and washed with diethyl ether. The filtrate wasconcentrated in vacuo to afford the title compound as colorless oil(0.70 g, 85%): MS (ES+) m/z 127.0 (M+1).

Step 3. Preparation of tert-butyl4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-chloro-2-fluorobenzoate

Following the procedure as described in Example 342 Step 3 and makingvariations as required to replace bicyclo[4.1.0]heptan-1-ylmethanol withbicyclo[4.1.0]heptan-3-ylmethanol, the title compound was obtained as agum (1.15 g, 58%): MS (ES+) m/z 355.0, 357.0 (M+1).

Step 4. Preparation of tert-butyl4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate

Following the procedure as described in Example 342 Step 4 and makingvariations as required to replace tert-butyl4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate withtert-butyl4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-chloro-2-fluorobenzoate, thetitle compound was obtained as a brown oil (1.29 g, 99%, crude yield):MS (ES+) m/z 361.1 (M+1).

Step 5. Preparation of4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid

Following the procedure as described in Example 332 Step 6, and makingvariations as required to replace tert-butyl4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate withtert-butyl4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate, thetitle compound was obtained as a yellow solid (1.06 g, 99%): MS (ES+)m/z 305.1 (M+1).

Step 6. Preparation of4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as a yellow solid (0.031 g, 17%):¹H NMR (300 MHz, CDCl₃) δ 8.71 (d, J=16.4 Hz, 1H), 7.58 (d, J=9.1 Hz,1H), 6.59 (d, J=14.5 Hz, 1H), 5.79-5.54 (m, 2H), 3.96-3.87 (m, 2H), 3.42(s, 2H), 2.37-1.68 (m, 7H), 1.42-1.19 (m, 2H), 1.06-0.99 (m, 2H),0.96-0.91 (m, 2H), 0.69-0.64 (m, 2H); MS (ES−) m/z 380.1 (M−1).

Example 362 Synthesis of4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoicacid and making variations as required to replace methanesulfonamidewith cyclopropanesulfonamide, the title compound was obtained as a solid(0.043 g, 21%): ¹H NMR (300 MHz, CDCl₃) δ8.69 (d, J=16.4 Hz, 1H), 7.58(d, J=9.1 Hz, 1H), 6.59 (d, J=14.5 Hz, 1H), 5.78-5.54 (m, 2H), 3.94-3.84(m, 2H), 3.15-3.06 (m, 1H), 1.96-1.68 (m, 7H), 1.48-1.40 (m, 2H),1.26-1.11 (m, 2H), 1.06-0.99 (m, 2H), 0.96-0.90 (m, 2H), 0.69-0.64 (m,2H); MS (ES+) m/z 408.0 (M+1).

Example 363 Synthesis ofN-(azetidin-1-ylsulfonyl)-4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2- fluorobenzoicacid and making variations as required to replace methanesulfonamidewith azetidine-1-sulfonamide, the title compound was obtained as solid(0.026 g, 5%): ¹H NMR (300 MHz, CDCl₃) δ 8.66 (d, J=16.5 Hz, 1H), 7.60(d, J=9.1 Hz, 1H), 6.59 (d, J=14.5 Hz, 1H), 5.78-5.54 (m, 2H), 4.25 (t,J=7.7 Hz, 4H), 3.96-3.85 (m, 2H), 2.35-2.17 (m, 4H), 2.11-1.64 (m, 5H),1.28-1.23 (m, 1H), 1.06-1.00 (m, 2H), 0.96-0.91 (m, 2H), 0.70-0.66 (m,2H); MS (ES+) m/z 423.1 (M+1).

Example 364 Synthesis of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(spiro[5.5]undecan-3-yloxy)benzamide

Step 1. Preparation of tert-butyl5-chloro-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzoate

Following the procedure as described in Example 342 Step 3 and makingvariations as required to replace bicyclo[4.1.0]heptan-1-ylmethanol withspiro[5.5]undecan-3-ol, the title compound was obtained as a colourlessgum (0.41 g, 35%): MS (ES+) m/z 397.1, 399.1 (M+1).

Step 2. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzoate

Following the procedure as described in Example 342 Step 4 and makingvariations as required to replace tert-butyl4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate withtert-butyl 5-chloro-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzoate, thetitle compound was obtained as an orange oil (0.33 g, 79%): MS (ES+) m/z403.1 (M+1).

Step 3. Preparation of 5-cyclopropyl-2-fluoro-4-(spiro[5.5]undecan-3yloxy)benzoic acid

Following the procedure as described in Example 332 Step 6, and makingvariations as required to replace tert-butyl4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoatewith tert-butyl5-cyclopropyl-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzoate, the titlecompound was obtained as a beige solid (0.23 g, 82%): MS (ES+) m/z 347.1(M+1).

Step 4. Preparation of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(spiro[5.5]undecan-3-yloxy)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-cyclopropyl-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzoic acid,the title compound was obtained as a white solid (0.022 g, 23%): ¹H NMR(300 MHz, DMSO-d₆) δ11.85 (s, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.00 (d,J=13.3 Hz, 1H), 4.62-4.53 (m, 1H), 2.74-2.55 (m, 2H), 2.45-2.25 (m, 1H),2.07-1.98 (m, 2H), 1.83-1.72 (m, 2H), 1.68-1.49 (m, 4H), 1.39-1.23 (m,11H), 0.91-0.83 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 424.1 (M+1).

Example 365 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-cyclopropyl-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzoic acidand making variations as required to replace methanesulfonamide withazetidine-1-sulfonamide, the title compound was obtained as a whitesolid (0.045 g, 44%): ¹H NMR (300 MHz, DMSO-d₆) δ11.57 (s, 1H), 7.13 (d,J=8.5 Hz, 1H), 7.00 (d, J=13.3 Hz, 1H), 4.62-4.54 (m, 1H), 4.04 (t,J=7.8 Hz, 4H), 2.74-2.55 (m, 2H), 2.29-1.97 (m, 2H), 1.84-1.73 (m, 2H),1.69-1.51 (m, 4H), 1.38-1.23 (m, 11H), 0.90-0.86 (m, 2H), 0.70-0.65 (m,2H); MS (ES+) m/z 465.1 (M+1).

Example 366 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-cyclopropyl-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzoic acid,and making variations as required to replace methanesulfonamide withcyclopropanesulfonamide, the title compound was obtained as a whitesolid (0.034 g, 34%): ¹H NMR (300 MHz, DMSO-d₆) δ11.78 (s, 1H), 7.12 (d,J=8.5 Hz, 1H), 7.00 (d, J=13.3 Hz, 1H), 4.61-4.55 (m, 1H), 3.11-3.03 (m,1H), 2.08-1.99 (m, 1H), 1.84-1.73 (m, 2H), 1.68-1.50 (m, 4H), 1.38-1.23(m, 11H), 1.12-1.07 (m, 5H), 0.92-0.85 (m, 2H), 0.69-0.64 (m, 2H); MS(ES+) m/z 450.1 (M+1).

Example 367 Synthesis ofN-(azetidin-1-ylsulfonyl)-4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide

Step 1. Preparation of tert-butyl4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-chloro-2-fluorobenzoate

Following the procedure as described in Example 342 step 3 and makingvariations as required to replace bicyclo[4.1.0]heptan-1-ylmethanol withbicyclo[3.1.0]hexan-3-ylmethanol, the title compound was obtained as acolorless gum (1.70 g, 62%): ¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J=6.8Hz, 1H), 6.55 (d, J=12.2 Hz, 1H), 3.75 (d, J=7.3 Hz, 2H), 2.29-2.12 (m,2H), 1.55 (s, 9H), 1.37-1.26 (m, 4H), 0.70-0.58 (m, 1H), 0.04-0.03 (m,1H); MS (ES+) m/z 341.0, 343.0 (M+1).

Step 2. Preparation of tert-butyl4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate

Following the procedure as described in Example 342 Step 4 and makingvariations as required to replace tert-butyl4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate withtert-butyl4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-chloro-2-fluorobenzoate, the titlecompound was obtained as a colourless solid (1.20 g, 70% yield): ¹H NMR(300 MHz, CDCl₃) δ 7.35 (d, J=8.4 Hz, 1H), 6.43 (d, J=12.7 Hz, 1H), 3.78(d, J=7.4 Hz, 2H), 2.88-2.74 (m, 2H), 2.16-2.07 (m, 1H), 1.98-1.89 (m,1H), 1.55 (s, 9H), 1.50 (d, J=4.5 Hz, 1H), 1.46 (d, J=4.5 Hz, 1H),1.30-1.25 (m, 2H), 0.88-0.82 (m, 2H), 0.58-0.53 (m, 2H), 0.09-0.05 (m,1H); MS (ES+) m/z 369.1 (M+23).

Step 3. Preparation of4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid

Following the procedure as described in Example 332 Step 6, and makingvariations as required to replace tert-butyl4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoatewith tert-butyl4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate, thetitle compound was obtained as a solid (0.32 g, 22% yield): MS (ES+) m/z291.1 (M+1).

Step 4. Preparation ofN-(azetidin-1-ylsulfonyl)-4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid with4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acidand to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained as a white solid (0.037 g, 27%): ¹H NMR (300MHz, CDCl₃) δ11.60 (br, s, 1H), 7.13 (d, J=8.31 Hz, 1H), 6.94 (d,J=12.98 Hz, 1H), 4.11-3.96 (m, 4H), 3.83 (d, J=7.42 Hz, 2H), 2.83-2.67(m, 1H), 2.25-2.07 (m, 4H), 2.05-1.92 (m, 1H), 1.58-1.45 (m, 2H),1.37-1.26 (m, 2H), 0.94-0.82 (m, 2H), 0.72-0.54 (m, 3H), 0.14-0.06 (m,1H); MS (ES+) m/z 409.1 (M+1).

Example 368 Synthesis of4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace 4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid with4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid,the title compound was obtained as a white solid (0.040 g, 32%): ¹H NMR(300 MHz, CDCl₃) δ11.85 (br, s, 1H), 7.09 (d, J=8.37 Hz, 1H), 6.90 (d,J=13.11 Hz, 1H), 3.3 (s, 3H), 3.79 (d, J=7.43 Hz, 2H), 2.78-2.63 (m,1H), 2.20-2.03 (m, 2H), 2.03-1.88 (m, 1H), 1.55-1.40 (m, 2H), 1.34-1.22(m, 2H), 0.90-0.78 (m, 2H), 0.68-0.49 (m, 3H), 0.11-0.02 (m, 1H); MS(ES+) m/z 368.1 (M+1).

Example 369 Synthesis of4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-ylmethoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid with4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acidand to replace methanesulfonamide with cyclopropanesulfonamide, thetitle compound was obtained as a white solid (0.046 g, 34%): ¹H NMR (300MHz, CDCl₃) δ11.80 (s, 1H), 7.08 (d, J=8.35 Hz, 1H), 6.90 (d, J=13.11Hz, 1H), 3.83-3.74 (m, 2H), 3.08-2.97 (m, 1H), 2.78-2.64 (m, 1H),2.19-2.04 (m, 2H), 2.02-1.88 (m, 1H), 1.54-1.42 (m, 2H), 1.33-1.22 (m,2H), 1.13-1.01 (m, 4H), 0.90-0.79 (m, 2H), 0.67-0.51 (m, 3H), 0.10-0.03(m, 1H); MS (ES+) m/z 394.1 (M+1).

Example 370 Synthesis ofN-(azetidin-1-ylsulfonyl)-4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-ylmethoxy)-5-chloro-2-fluorobenzamide

Step 1. Preparation of4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-ylmethoxy)-5-chloro-2-fluorobenzoicacid

Following the procedure as described in Example 342 Step 6, and makingvariations as required to replace tert-butyl4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoatewith tert-butyl4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-ylmethoxy)-5-chloro-2-fluorobenzoate,the title compound was obtained as a solid (0.048 g, 4%): MS (ES−) m/z283.2 (M−1).

Step 2. Preparation ofN-(azetidin-1-ylsulfonyl)-4-((1R,3r,5S)-bicyclo[3.1.0]-hexan-3-ylmethoxy)-5-chloro-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-chloro-2-fluorobenzoic acidand to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained as a white solid (0.044 g, 22%): ¹H NMR (300MHz, CDCl₃) δ11.83 (br s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.23 (d, J=12.4Hz, 1H), 4.12-3.97 (m, 3H), 3.90 (d, J=7.37 Hz, 1H), 3.3 (m, 2H),2.81-2.66 (m, 1H), 2.25-2.07 (m, 3H), 1.55-1.44 (m, 2H), 1.37-1.26 (m,2H), 1.05-1.15 (m, 1H), 0.65-0.52 (m, 1H), 0.18-0.10 (m, 1H); MS (ES+)m/z 403.1, 405.1 (M+1).

Example 371 Synthesis of4-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-ylmethoxy)-5-chloro-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-chloro-2-fluorobenzoic acidand making variations as required to replace methanesulfonamide withcyclopropanesulfonamide, the title compound was obtained as a whitesolid (0.0035 g, 18%): ¹H NMR (300 MHz, CDCl₃) δ12.04 (br, s, 1H), 7.75(d, J=7.53 Hz, 1H), 7.23 (d, J=12.55 Hz, 1H), 3.96-3.84 (m, 2H),3.13-2.99 (m, 1H), 2.82-2.65 (m, 1H), 2.23-2.05 (m, 2H), 1.56-1.44 (m,2H), 1.38-1.20 (m, 2H), 1.18-1.05 (m, 3H), 0.94-0.77 (m, 1H), 0.67-0.52(m, 1H), 0.18-0.09 (m, 1H); MS (ES+) m/z 388.0 (M+1).

Example 372 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide withazetidine-1-sulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acid, thetitle compound was obtained as a colorless solid (0.028 g, 19%): ¹H NMR(300 MHz, DMSO-d₆) δ 11.80 (br s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.38 (d,J=12.4 Hz, 1H), 4.85 (br s, 1H), 4.00 (t, J=7.7, 7.7 Hz, 4H), 2.18-1.86(m, 10H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −92.2 (d, J=231 Hz, 1F), −98.5(d, J=231 Hz, 1F), −110.1 (s, 1F); MS (ES−) m/z 425.1, 427.1 (M−1).

Example 373 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzamide

Step 1. Preparation of methyl5-cyclopropyl-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoate

To an argon-degassed solution of methyl5-chloro-4-((4,4-difluoro-cyclohexyl)oxy)-2-fluorobenzoate (0.394 g,1.22 mmol) in toluene (15 mL) and water (3 mL) was addedcyclopropylboronic acid (0.639 g, 7.44 mmol), tribasic potassiumphosphate (0.826 g, 3.89 mmol), tricyclohexylphosphine tetrafluoroborate(0.30 g, 0.97 mmol), and palladium acetate trimer (0.108 g, 0.481 mmolPd). The mixture was heated to reflux under an argon atmosphere for 21hours, cooled to ambient temperature. The mixture was filtered through apad of diatomaceous earth that was rinsed with ethyl acetate (100 mL).The filtrate was washed with a 2:1 mixture of saturated aqueous ammoniumchloride and water (150 mL), brine (150 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo to dryness. Theresidue was purified by column chromatography with a gradient of ethylacetate in hexanes (0-10%) to afford the title compound as a lightyellow syrup (0.30 g, 76%): ¹H NMR (300 MHz, CDCl₃) δ 7.46 (d, J=8.4 Hz,1H), 6.55 (d, J=12.6 Hz, 1H), 4.57 (br s, 1H), 3.86 (s, 3H), 2.44-1.88(m, 9H), 0.93-0.86 (m, 2H), 0.64-0.59 (m, 2H); ¹⁹F NMR (282 MHz, CDCl₃)8-92.3 (d, J=238 Hz, 1F), −102.3 (d, J=237 Hz, 1F), −109.4 (s, 1F); MS(ES+) m/z 329.1 (M+1).

Step 2. Preparation of5-cyclopropyl-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acid

Following the procedure as described in Example 332 Step 6, and makingvariations as required to replace tert-butyl4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate withmethyl 5-cyclopropyl-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoate,the title compound was obtained as a colorless solid (0.32 g, quant.yield): ¹H NMR (300 MHz, CDCl₃) δ 7.54 (d, J=8.4 Hz, 1H), 6.58 (d,J=12.7 Hz, 1H), 4.60 (br s, 1H), 2.20-1.92 (m, 9H), 0.94-0.88 (m, 2H),0.65-0.60 (m, 2H); MS (ES−) m/z 313.2 (M−1).

Step 3. Preparation of5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-cyclopropyl-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acidand to replace methanesulfonamide with cyclopropanesulfonamide, thetitle compound was obtained as a colorless solid (0.093 g, 48%): ¹H NMR(300 MHz, DMSO-d₆) δ 11.79 (br s, 1H), 7.13-7.06 (m, 2H), 4.78 (br s,1H), 3.08-2.99 (m, 1H), 2.08-1.86 (m, 9H), 1.09-1.06 (m, 4H), 0.88-0.82(m, 2H), 0.66-0.60 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −92.1 (d, J=231Hz, 1F), −98.5 (d, J=231 Hz, 1F), −112.5 (s, 1F); MS (ES−) m/z 416.10(M−1).

Example 373a Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide withcyclopropanesulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-cyclopropyl-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acidand to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained as a colorless solid (0.092 g, 46%): ¹H NMR(300 MHz, DMSO-d₆) δ 11.58 (br s, 1H), 7.14-7.06 (m, 2H), 4.80 (br s,1H), 4.00 (t, J=7.7, 7.7 Hz, 4H), 2.18-1.87 (m, 11H), 0.89-0.82 (m, 2H),0.67-0.61 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −92.0 (d, J=232 Hz, 1F),−98.5 (d, J=231 Hz, 1F), −112.7 (s, 1F); MS (ES−) m/z 431.1 (M−1).

Example 374 Synthesis of4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of 1-(hydroxymethyl)cyclohexanecarbonitrile

To a solution of methyl 1-cyanocyclohexanecarboxylate (preparedaccording to Fleming et. al, J. Org. Chem. 2005, 70, 2200) (8.54 g,51.10 mmol) in anhydrous tetrahydrofuran (300 mL) was added anhydrousmethanol (3.1 mL, 78.00 mmol) and lithium borohydride (4.0 M solution intetrahydrofuran 19 mL, 76 mmol). The reaction solution was heated toreflux under a nitrogen atmosphere for 4 hours, cooled to ambienttemperature. The mixture was quenched by the slow addition of saturatedaqueous ammonium chloride (5 mL). The mixture was diluted with ethylacetate (400 mL), washed with a 2:1 mixture of saturated aqueousammonium chloride and water (2×300 mL), dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to afford the title compoundas a colorless oil (6.30 g, 89%): ¹H NMR (300 MHz, CDCl₃) δ 3.55 (s,2H), 2.78 (br s, 1H), 1.98-1.93 (m, 2H), 1.74-1.69 (m, 4H), 1.63-1.48(m, 4H).

Step 2. Preparation of tert-butyl5-chloro-4-((1-cyanocyclohexyl)methoxy) 2-fluorobenzoate

To a solution of 1-(hydroxymethyl)cyclohexanecarbonitrile (3.04 g, 21.80mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (6.30 g, 25.30 mmol)in dimethylsulfoxide (40 mL) was added cesium carbonate (14.35 g, 44.00mmol). The mixture was heated at 80° C. under a nitrogen atmosphere for3.5 hours, cooled to ambient temperature. The mixture was quenched with1 M hydrochloric acid (70 mL), then diluted with ethyl acetate (350 mL),washed with 1 M hydrochloric acid (2×350 mL), brine (2×350 mL), driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo.The residue was purified by column chromatography, with a gradient ofethyl acetate in hexanes from 0-10% to afford the title compound as acolorless solid (3.87 g, 48%): ¹H NMR (300 MHz, CDCl₃) δ 7.87 (d, J=7.6Hz, 1H), 6.60 (d, J=11.6 Hz, 1H), 3.97 (s, 2H), 2.16-2.11 (m, 2H),1.82-1.63 (m, 5H), 1.59-1.42 (m, 11H), 1.29-1.21 (m, 1H); MS (ES+) m/z368.0, 370.0 (M+1).

Step 3. Preparation of tert-butyl4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoate

To an argon-degassed solution of tert-butyl5-chloro-4-((1-cyano-cyclohexyl)methoxy)-2-fluorobenzoate (0.571 g, 1.55mmol) in toluene (8 mL) and water (1 mL) was added cyclopropylboronicacid (0.66 g, 7.71 mmol), tribasic potassium phosphate (1.02 g, 4.80mmol), tricyclohexylphosphine tetrafluoroborate (0.28 g, 0.92 mmol), andpalladium acetate trimer (0.11 g, 0.47 mmol Pd). The mixture was heatedat 150° C. in a microwave reactor for 0.5 hour, then diluted with ethylacetate (150 mL), washed with a 3:1 mixture of saturated aqueousammonium chloride and water (2×150 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo to dryness. The residue waspurified by column chromatography with a gradient of ethyl acetate inhexanes from 0-10% to afford the title compound as a yellow syrup (0.50g, 86%): ¹H NMR (300 MHz, CDCl₃) δ 7.41 (d, J=8.3 Hz, 1H), 6.46 (d,J=12.2 Hz, 1H), 3.93 (s, 2H), 2.18-2.13 (m, 2H), 2.07-1.98 (m, 1H),1.82-1.63 (m, 5H), 1.55 (s, 9H), 1.48-1.39 (m, 2H), 1.29-1.21 (m, 1H),0.94-0.88 (m, 2H), 0.65-0.60 (m, 2H); MS (ES+) m/z 374.0 (M+1).

Step 4. Preparation of4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid

To a solution of tert-butyl4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoate (0.498 g,1.33 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (5mL). The solution was stirred at ambient temperature for 1 hour and thesolvent was concentrated in vacuo to dryness. The residue was trituratedwith diethyl ether (10 mL) to afford the title compound as a colorlesssolid (0.32 g, 75%): ¹H NMR (300 MHz, DMSO-d₆) 12.88 (br s, 1H), 7.32(d, J=8.4 Hz, 1H), 6.93 (d, J=12.8 Hz, 1H), 4.14 (s, 2H), 2.02-1.95 (m,3H), 1.72-1.65 (m, 3H), 1.51-1.43 (m, 4H), 1.24-1.18 (m, 1H), 0.91-0.85(m, 2H), 0.61-0.56 (m, 2H); MS (ES−) m/z 316.2 (M−1).

Step 5. Preparation of4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid,the title compound was obtained as a colorless solid (0.087 g, 67%): ¹HNMR (300 MHz, DMSO-d₆) δ11.93 (br s, 1H), 7.14 (d, J=8.2 Hz, 1H), 6.99(d, J=12.8 Hz, 1H), 4.15 (s, 2H), 3.31 (s, 3H), 2.04-1.96 (m, 3H),1.73-1.66 (m, 3H), 1.51-1.38 (m, 4H), 1.24-1.16 (m, 1H), 0.91-0.85 (m,2H), 0.69-0.64 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −112.6 (s, 1F); MS(ES−) m/z 393.2 (M−1).

Example 375 Synthesis of4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidand making variations as required to replace methanesulfonamide withcyclopropanesulfonamide, the title compound was obtained as a colorlesssolid (0.092 g, 66% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 11.86 (br s,1H), 7.13 (d, J=8.2 Hz, 1H), 6.99 (d, J=12.8 Hz, 1H), 4.15 (s, 2H),3.08-3.00 (m, 1H), 2.03-1.95 (m, 3H), 1.73-1.66 (m, 3H), 1.51-1.38 (m,4H), 1.23-1.15 (m, 1H), 1.09-1.05 (m, 4H), 0.91-0.85 (m, 2H), 0.69-0.64(m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −112.3 (s, 1F); MS (ES−) m/z 419.2(M−1).

Example 376 Synthesis ofN-(azetidin-1-ylsulfonyl)-4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidand to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained as a colorless solid (0.061 g, 42%): ¹H NMR(300 MHz, DMSO-d₆) δ 11.65 (br s, 1H), 7.14 (d, J=8.1 Hz, 1H), 6.99 (d,J=12.6 Hz, 1H), 4.15 (s, 2H), 4.02 (t, J=7.6, 7.6 Hz, 4H), 2.18-2.08 (m,2H), 2.03-1.97 (m, 3H), 1.73-1.66 (m, 3H), 1.51-1.39 (m, 4H), 1.20 (brs, 1H), 0.91-0.85 (m, 2H), 0.69-0.64 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ −112.6 (s, 1F); MS (ES−) m/z 434.1 (M−1).

Example 377 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((4-fluorobicyclo[4.1.0]heptan-1-yl)methoxy)benzamide

Step 1. Preparation of ethyl 8-(phenylselanyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate

To a solution of diisopropylethyl amine (5.59 g, 55.30 mmol) inanhydrous tetrahydrofuran (150 mL) was added a solution of butyllithium(1.6 M in hexanes, 34.5 mL, 55.30 mmol) at 0° C. The reaction solutionwas stirred at the same temperature for 1 hour, then added a solution ofethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (10.80 g, 50.00 mmol) inanhydrous tetrahydrofuran (20 mL) at −78° C. The reaction mixture wasstirred at the same temperature for 1 h then added phenylseleniumbromide (11.90 g, 50.70 mmol). The mixture was continued to stir at −78°C. for 5 hour, then at ambient temperature for 16 hour. The reaction wasquenched with saturated sodium hydrogencarbonate (200 mL), diluted withethyl acetate (200 mL), saturated ammonium chloride (3×150 mL), brine(3×100 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was purifiedby column chromatography with ethyl acetate in hexanes (10%) to affordthe title compound as a viscous liquid (14.10 g, 76%): ¹H NMR (300 MHz,CDCl₃) δ 7.54 (d, J=7.6 Hz, 1H), 7.37-7.32 (m, 1H), 7.26 (dd, J=7.0, 7.0Hz, 2H), 4.05 (dd, J=7.1 Hz, 2H), 3.90 (d, J=3.4 Hz, 4H), 2.20-2.12 (m,2H), 2.00-1.88 (m, 2H), 1.82-1.70 (m, 2H), 1.57-1.46 (m, 2H), 1.14 (t,J=7.1 Hz, 3H).

Step 2. Preparation of ethyl 1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate

To a solution of ethyl8-(phenylselanyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (14.00 g,38.00 mmol) in dichloromethane (100 mL) was added 30% hydrogen peroxidesolution (11.6 mL, 380.0 mmol). The reaction mixture was stirred atambient temperature for 16 h then diluted with dichloromethane (100 mL),washed with saturated sodium hydrogencarbonate (100 mL), saturatedammonium chloride (3×75 mL), and brine (3×75 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo todryness. The residue was purified by column chromatography with ethylacetate in hexanes (10%) to afford the title compound as a colorlessliquid (6.10 g, 76%): ¹H NMR (300 MHz, CDCl₃) δ 6.82 (m, 1H), 4.11 (dd,J=7.1 Hz, 2H), 3.92 (s, 4H), 2.49-2.43 (m, 2H), 2.34-2.29 (m, 2H),1.76-1.65 (m, 4H), 1.21 (t, J=7.1 Hz, 3H).

Step 3. Preparation of 1,4-dioxaspiro[4.5]dec-7-en-8-ylmethanol

Following the procedure as described in Example 361 Step 2 and makingnon-critical variations to replace methylbicyclo[4.1.0]heptane-3-carboxylate with ethyl1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate, the title compound wasobtained as a colourless liquid (5.0 g, 94%): ¹H NMR (300 MHz, CDCl₃) δ5.62-5.57 (m, 1H), 4.04-3.91 (m, 6H), 3.47 (d, J=6.4 Hz, 1H), 2.31-2.20(m, 4H), 1.82-1.71 (m, 4H).

Step 4. Preparation ofspiro[bicyclo[4.1.0]heptane-3,2′-[1,3]dioxolane]-6-ylmethanol

Following the procedure as described in Example 342 Step 2 and makingnon-critical variations to replace cyclohexenylmethanol with1,4-dioxaspiro[4.5]dec-7-en-8-ylmethanol, the title compound wasobtained as a colourless liquid (4.0 g, 96%): ¹H NMR (300 MHz, CDCl₃) δ3.92-3.84 (m, 4H), 3.48 (d, J=10.8 Hz, 1H), 3.26 (d, J=10.9 Hz, 1H),2.21-2.0 (m, 2H), 1.94-1.86 (m 1H), 1.77-1.65 (m, 1H), 1.60-1.51 (m,1H), 1.40-1.30 (m, 1H), 0.58 (dd, J=9.2, 4.8 Hz, 1H), 0.40 (t, J=5.0 Hz,1H).

Step 5. Preparation of tert-butyl5-chloro-2-fluoro-4-(spiro[bicycle-[4.1.0]heptane-3,2′-[1,3]dioxolan]-6-ylmethoxy)benzoate

Following the procedure as described in Example 342 step 3 and makingvariations as required to replace bicyclo[4.1.0]heptan-1-ylmethanolspiro[bicyclo[4.1.0]heptane-3,2′-[1,3]dioxolane]-6-ylmethanol, the titlecompound was obtained as a colorless gum (1.40 g, 56%): ¹H NMR (300 MHz,CDCl₃) δ 7.85 (d, J=7.7 Hz, 1H), 6.54 (d, J=12.2 Hz, 1H), 3.99-3.82 (m,6H), 3.73 (d, J=9.2 Hz, 1H), 2.14-2.04 (m 2H), 1.80-1.72 (m, 2H),1.64-1.57 (m, 2H), 1.55 (s, 9H), 1.46-1.34 (m, 2H), 1.12-1.03 (m, 1H),0.81-0.76 (m, 1H), 0.59 (t, J=5.3 Hz, 1H); MS (ES+) m/z 435.0, 437.0(M+23).

Step 6. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-(spiro[bicyclo[4.1.0]heptane-3,2′-[1,3]dioxolan]-6-ylmethoxy)benzoate

Following the procedure as described in Example 342 Step 4 and makingvariations as required to replace tert-butyl4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate oftert-butyl5-chloro-2-fluoro-4-(spiro[bicyclo[4.1.0]heptane-3,2′-[1,3]dioxolan]-6-ylmethoxy)benzoate,the title compound was obtained as a colorless solid (1.30 g, 93%): ¹HNMR (300 MHz, CDCl₃) δ 7.35 (d, J=8.3 Hz, 1H), 6.42 (d, J=12.7 Hz, 1H),3.95-3.86 (m, 4H), 3.84-3.70 (m, 2H), 2.22-1.98 (m, 4H), 1.82-1.72 (m,2H), 1.64-1.57 (m, 2H), 1.56 (s, 9H), 1.49-1.35 (m, 2H), 1.11-1.04 (m,1H), 0.80-0.75 (m, 11H), 0.65-0.60 (m, 1H), 0.56 (t, J=5.3 Hz, 1H); MS(ES+) m/z 419.2 (M+1).

Step 7. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((4-oxobicyclo[4.1.0]-heptan-1-yl)methoxy)benzoate

To a solution of tert-butyl5-cyclopropyl-2-fluoro-4-(spiro[bicyclo[4.1.0]heptane-3,2′-[1,3]dioxolan]-6-ylmethoxy)benzoate(0.61 g, 1.86 mmol) in tetrahydrofuran (2.0 mL) was added water (2.0 mL)followed by trifluoroacetic acid (0.75 g, 6.56 mmol). The reactionsolution was stirred at ambient temperature for 16 hours. The reactionmixture was diluted with ethyl acetate (20 mL), washed with a solutionof aqueous sodium hydroxide (2.0 mL, 3 M). The organic layer wasseparated and concentrated in vacuo to afford the title compound as acolorless gum (0.63 g, quant.): ¹H NMR (300 MHz, CDCl₃) δ 7.36 (d, J=8.4Hz, 1H), 6.43 (d, J=12.6 Hz, 1H), 3.91 (d, J=9.3 Hz, 1H), 3.71 (d, J=9.3Hz, 1H), 2.72 (dd, J=18.4, 5.4 Hz, 1H), 2.56-2.32 (m, 4H), 2.20-2.07 (m,2H), 1.99-1.92 (m, 1H), 1.53 (s, 9H), 1.21-0.79 (m, 5H), 0.70 (t, J=5.3Hz, 1H), 0.63-0.58 (m, 2H); MS (ES+) m/z 397.2 (M+23).

Step 8. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((4-hydroxybicyclo-[4.1.0]heptan-1-yl)methoxy)benzoate

To a solution of tert-butyl5-cyclopropyl-2-fluoro-4-((4-oxobicyclo[4.1.0]heptan-1-yl)methoxy)benzoate(0.63 g, 1.70 mmol) was dissolved in 1,2- dimethoxyethane (5 mL), sodiumborohydride (0.13 g, 3.40 mmol) was added. The reaction mixture wasstirred for 0.5 hour and quenched with slow addition of water (5 mL)followed by ethyl acetate (10 mL). To this reaction mixture was addedconcentrated hydrochloride (37%, 1.0 mL) and stirred for 10 minutes. Theorganic layer was separated and the solvent was concentrated in vacuo toafford the title compound as a solid (0.13 g, 19%): ¹H NMR (300 MHz,CDCl₃) (7.36 (d, J=8.5 Hz, 1H), 6.40 (d, J=12.7 Hz, 1H), 3.78 (d, J=9.2Hz, 1H), 3.62 (d, J=9.4 Hz, 1H), 2.40-2.30 (m, 4H), 2.20-2.07 (m, 2H),1.99-1.92 (m, 1H), 1.53 (s, 9H), 1.42-1.33 (m, 1H), 1.29-1.09 (m, 2H),0.89-0.82 (m, 4H), 0.76-0.71 (m, 1H, 0.65-0.60 (m, 2H), 0.47 (t, J=5.3Hz, 1H); MS (ES+) m/z 377.2 (M+1).

Step 9. Preparation of5-cyclopropyl-2-fluoro-4-((4-fluorobicyclo[4.1.0]heptan-1-yl)methoxy)benzoicacid

To a solution of tert-butyl5-cyclopropyl-2-fluoro-4-((4-hydroxybicyclo-[4.1.0]heptan-1-yl)methoxy)benzoate(0.13 g, 0.41 mmol) in chloroform (2 mL) was added diethylaminosulfurtrifluoride (0.11 mL, 0.89 mmol). The reaction solution was stirred atambient temperature for 16 h and quenched with slow addition of aqueoussaturated sodium hydrogencarbonate. The reaction mixture was extractedwith dichloromethane. The solvent was concentrated in vacuo to dryness.The residue (0.10 g) was dissolved in dichloromethane (1 mL) andtrifluoroacetic acid (0.15 g, 1.30 mmol) was added. The reaction mixturewas stirred for 2 h and the solvent was concentrated in vacuo to obtainthe title compound as a gum (0.080 g, 95%). The residue was carriedforward without any further purification in next reaction: MS (ES−) m/z321.1 (M−1).

Step 10. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((4-fluorobicyclo[4.1.0]heptan-1-yl)methoxy)benzamide

Following the procedure as described in Example 339 Step 4 and makingnon-critical variations to replace5-chloro-4-(cyclohexyloxymethyl)-2-fluorobenzoic acid with5-cyclopropyl-2-fluoro-4-((4-fluorobicyclo[4.1.0]heptan-1-yl)methoxy)benzoicacid, the title compound was obtained following purification byreverse-phase HPLC as a colorless powder (0.007 g, 6%): ¹H NMR (300 MHz,CDCl₃) δ 8.65 (d, J=16.3 Hz, 1H), 7.60 (d, J=9.1 Hz, 1H), 6.51 (d,J=14.1 Hz, 1H), 4.80-4.42 (m, 2H), 4.35-4.09 (m, 3H), 4.31-4.14 (m, 1H),3.86-3.78 (m, 1H), 2.40-1.61 (m, 7H), 1.61-1.13 (m, 1H), 1.14-0.58 (m,7H), 0.44-0.31 (m, 1H); MS (ES−) m/z 441.1 (M+1).

Example 378 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Synthesis of tert-butyl4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoate

Following the procedure as described in Example 373 Step 1 and makingnon-critical variations to replace tert-butyl5-chloro-4-((1-cyanocyclohexyl)-methoxy)-2-fluorobenzoate withtert-butyl 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoate, toreplace cyclopropylboronic acid with cyclobutylboronic acid, and toreplace tricyclohexylphosphine tetrafluoroborate with2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos), the titlecompound was obtained as a colorless syrup containing ˜25% tert-butyl4-(adamantan-1-ylmethoxy)-2-fluorobenzoate (1.01 g, 97%): MS (ES+) m/z359.1 (M−55).

Step 2. Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoic acid

Following the procedure as described in Example 373 Step 2 makingnon-critical variations to replace tert-butyl4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoate withtert-butyl 4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoate, thetitle compound was obtained as a yellow solid (0.65 g, 76%). The solidwas carried forward without further purification and analyticalcharacterization.

Step 3. Preparation of4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace 4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid with4-((3r,5r,7r)-adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoic acid,the title compound was obtained as a colorless solid (0.017 g, 4%): ¹HNMR (300 MHz, DMSO-d₆) δ11.89 (br s, 1H), 7.40 (d, J=8.4 Hz, 1H), 6.88(d, J=13.2 Hz, 1H), 3.56 (s, 3H), 3.31 (s, 3H), 2.33-2.21 (m, 2H),2.15-1.96 (m, 6H), 1.81-1.60 (m, 13H); MS (ES−) m/z 434.2 (M−1).

Example 379 Synthesis of4-(adamantan-1-ylmethoxy)-5-cyclobutyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoic acid and toreplace methanesulfonamide with cyclopropanesulfonamide, the titlecompound was obtained as a colorless solid (0.090 g, 35%): ¹H NMR (300MHz, CDCl₃) δ 8.69 (d, J=16.3 Hz, 1H), 7.87 (d, J=9.3 Hz, 1H), 6.53 (d,J=14.71H), 3.69-3.56 (m, 1H), 3.49 (s, 2H), 3.15-3.06 (m, 1H), 2.39-2.29(m, 2H), 2.18-1.98 (m, 6H), 1.87-1.65 (m, 13H), 1.48-1.42 (m, 2H),1.17-1.10 (m, 2H); MS (ES−) m/z 460.2 (M−1).

Example 380 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-cyclobutyl-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoic acid and toreplace methanesulfonamide with azetidine-1-sulfonamide, the titlecompound was obtained as a colorless solid (0.043 g, 13%): ¹H NMR (300MHz, CDCl₃) δ 8.66 (d, J=16.5 Hz, 1H), 7.88 (d, J=9.3 Hz, 1H), 6.54 (d,J=14.6 Hz, 1H), 4.24 (t, J=7.7 Hz, 4H), 3.69-3.58 (m, 1H), 3.49 (s, 2H),2.39-1.99 (m, 10H), 1.87-1.64 (m, 13H); MS (ES−) m/z 475.2 (M−1).

Example 381 Synthesis of5-cyclopropyl-4-((1-(difluoromethyl)cyclohexyl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((l-formylcyclohexyl)-methoxy)benzoate

To a mixture of tert-butyl4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoate (1.00 g,2.70 mmol) in anhydrous toluene (11 mL) was added diisobutylaluminumhydride (1.0 M in toluene, 2.9 mL, 2.90 mmol) at −78° C. The resultingmixture stirred at −78° C. for 2.5 hours. The mixture was slowlyquenched with water (20 mL) at −78° C. and warmed to ambienttemperature. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate (50 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated in vacuoto dryness. The residue was purified by column chromatography with ethylacetate in hexanes (0-20%) to afford the title compound as a yellow oil(0.315 g, 31%): MS (ES+) m/z 321.0 (M−55).

Step 2. Preparation of tert-butyl5-cyclopropyl-4-((1-(difluoromethyl)cyclohexyl)-methoxy)-2-fluorobenzoate

Following the procedure as described in Example 357 Step 5 and makingvariations as required to replace methyl5-cyclopropyl-2-fluoro-4-((4-oxocyclohexyl)-methoxy)benzoate withtert-butyl 5-cyclopropyl-2-fluoro-4-((1-formyl-cyclohexyl)methoxy)benzoate, the title compound was obtained as anyellow oil (0.21 g, 98%): MS (ES+) m/z 421.1 (M+23).

Step 3. Preparation of5-cyclopropyl-4-((1-(difluoromethyl)-cyclohexyl)methoxy)-2-fluorobenzoicacid

Following the procedure as described in Example 332 Step 6, and makingvariations as required to replace tert-butyl4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate withtert-butyl5-cyclopropyl-4-((1-(difluoromethyl)-cyclohexyl)methoxy)-2-fluorobenzoate,the title compound was obtained as a beige solid (0.16 g, 96%): MS (ES+)m/z 343.1 (M+1).

Step 4. Preparation of5-cyclopropyl-4-((1-(difluoromethyl)cyclohexyl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-4-((1-(difluoromethyl)cyclohexyl)-methoxy)-2-fluorobenzoicacid, the title compound was obtained as a white solid (0.074 g, 75%):¹H NMR (300 MHz, DMSO-d₆) δ11.92 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.11(d, J=13.0 Hz, 1H), 6.04 (t, J=56.4 Hz, 1H), 4.14 (s, 2H), 2.07-2.00 (m,1H), 1.73-1.23 (m, 13H), 0.91-0.85 (m, 2H), 0.67-0.62 (m, 2H); MS (ES+)m/z 420.0 (M+1).

Example 382 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(difluoromethyl)-cyclohexyl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-4-((1-(difluoromethyl)cyclohexyl)-methoxy)-2-fluorobenzoicacid, and to replace methanesulfonamide with azetidine-1-sulfonamide,the title compound was obtained as a yellow oil (0.085 g, 79%): ¹H NMR(300 MHz, DMSO-d₆) δ11.64 (s, 1H), 7.17-7.10 (m, 2H), 6.04 (t, J=56.4Hz, 1H), 4.14 (s, 2H), 4.05 (t, J=7.7 Hz, 4H), 2.22-2.08 (m, 2H),2.06-1.98 (m, 1H), 1.74-1.65 (m, 2H), 1.59-1.44 (m, 7H), 1.32-1.21 (m,1H), 0.92-0.85 (m, 2H), 0.68-0.63 (m, 2H); MS (ES+) m/z 461.1 (M+1).

Example 383 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-(((1SR,6RS)-7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzamide

Step 1. Preparation of tert-butyl5-cyclopropyl-4-(((1SR,6RS)-7,7-difluorobicyclo[4.1.0]-heptan-1-yl)methoxy)-2-fluorobenzoate

Following the procedure as described in Example 342 Step 4 and makingvariations as required to replace tert-butyl4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate withtert-butyl 5-chloro-4-(((1SR,6RS)-7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoate(stereochemistry arbitrarily assigned), the title compound was obtainedas a yellow oil (0.18 g, 58%): MS (ES+) m/z 341.0 (M−55).

Step 2. Preparation of5-cyclopropyl-4-(((1SR,6RS)-7,7-difluoro-bicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoicacid (stereochemistry arbitrarily assigned)

Following the procedure as described in Example 332 Step 6, and makingvariations as required to replace tert-butyl4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate withtert-butyl 5-cyclopropyl-4-(((1SR,6RS)-7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoate(stereochemistry arbitrarily assigned) the title compound was obtainedas a beige solid (0.12 g, 79%): MS (ES+) m/z 341.0 (M+1).

Step 3. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-(((1SR,6RS)-7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-4-(((1SR,6RS)-7,7-difluorobicyclo-[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoicacid and to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained as a white gum (0.051 g, 81%): ¹H NMR (300MHz, CDCl₃) δ 8.65 (s, 1H), 7.64 (d, J=9.1 Hz, 1H), 6.54 (d, J=14.1 Hz,1H), 4.25 (t, J=7.9 Hz, 4H), 3.98 (s, 2H), 2.32-2.22 (m, 2H), 2.09-2.00(m, 1H), 1.96-1.57 (m, 4H), 1.49-1.25 (m, 5H), 0.98-0.92 (m, 2H),0.72-0.67 (m, 2H); MS (ES+) m/z 459.1 (M+1).

Example 384 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-4-(((1SR,6RS)-7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzamide(stereochemistry arbitrarily assigned)

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-4-(((1SR,6RS)-7,7-difluorobicyclo-[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoicacid and to replace methanesulfonamide with cyclopropanesulfonamide, thetitle compound was obtained as a white gum (0.053 g, 87%): ¹H NMR (300MHz, CDCl₃) δ8.68 (d, J=14.5 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 6.53 (d,J=14.1 Hz, 1H), 3.98 (s, 2H), 3.14-3.06 (m, 1H), 2.08-1.99 (m, 1H),1.95-1.92 (m, 2H), 1.87-1.71 (m, 2H), 1.49-1.43 (m, 2H), 1.40-1.25 (m,5H), 1.17-1.13 (m, 2H), 0.98-0.91 (m, 2H), 0.71-0.66 (m, 2H); MS (ES+)m/z 444.0 (M+1).

Example 385 Synthesis of5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-3-yl)-methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of methyl7,7-difluorobicyclo[4.1.0]heptane-3-carboxylate

Following the procedure as described in Example 347 Step 2 and makingnon-critical variations to replace1-((cyclohexenylmethoxy)methyl)-4-methoxybenzene with methylcyclohex-3-enecarboxylate, the title compound was obtained as acolorless liquid (0.50 g, 52%): ¹H NMR (300 MHz, CDCl₃) δ 3.65 (s, 3H),2.36-1.85 (m, 3H), 1.87-1.41 (m, 5H), 1.40-1.15 (m, 1H);

Step 2. Preparation of (7,7-difluorobicyclo[4.1.0]heptan-3-yl)methanol

Following the procedure as described in Example 342 Step 1 and makingnon-critical variations to replace methyl cyclohex-1-enecarboxylate with7,7-difluorobicyclo[4.1.0]-heptane-3-carboxylate, the title compound wasobtained as a colorless liquid (0.30 g, 70%): ¹H NMR (300 MHz, CDCl₃) δ3.50-3.23 (m, 2H), 2.50-2.25 (m, 1H), 2.15-1.76 (m, 2H), 1.74-0.96 (m,5H), 0.96-0.54 (m, 1H).

Step 3. Preparation of tert-butyl5-chloro-4-((7,7-difluorobicyclo[4.1.0]heptan-3-yl)methoxy)-2-fluorobenzoate

Following the procedure as described in Example 342 Step 3 and makingvariations as required to replace bicyclo[4.1.0]heptan-1-ylmethanol with(7,7-difluorobicyclo[4.1.0]heptan-3-yl)methanol, the title compound wasobtained as a colorless gum (0.48 g, 61%): MS (ES+) m/z 391.22 (M+1).

Step 4. Preparation of tert-butyl5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-3-yl)methoxy)-2-fluorobenzoate

Following the procedure as described in Example 342 Step 4 and makingvariations as required to replace tert-butyl4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate withtert-butyl5-chloro-4-((7,7-difluorobicyclo[4.1.0]heptan-3-yl)methoxy)-2-fluorobenzoate,the title compound was obtained as oil (0.35 g, 48%): MS (ES+) m/z341.07 (M−55).

Step 5. Preparation of5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-3-yl)methoxy)-2-fluorobenzoicacid

Following the procedure as described in Example 332 Step 6, and makingvariations as required to replace tert-butyl 4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoatewith tert-butyl5-cyclopropyl-4-((7,7-difluorobicyclo-[4.1.0]heptan-3-yl)methoxy)-2-fluorobenzoate,the title compound was obtained as solid (0.24 g, 78%): MS (ES+) m/z341.10 (M+1).

Step 6. Preparation of5-cyclopropyl-4-((7,7-difluorobicyclo-[4.1.0]heptan-3-yl)methoxy)2-fluoro-N-(methylsulfonyl)benzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]-heptan-3-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained as a white solid (0.035 g, 35%):¹H NMR (300 MHz, DMSO-d₆) δ11.88 (br s, 1H), 7.11 (d, J=8.33 Hz, 1H),7.03-6.85 (m, 1H), 4.21-3.68 (m, 2H), 2.97-2.51 (m, 3H), 2.36-1.05 (m,10H), 0.93-0.77 (m, 2H), 0.69-0.56 (m, 2H); MS (ES+) m/z 418.1 (M+1).

Example 386 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]-heptan-3-yl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-3-yl)methoxy)-2-fluorobenzoicacid and to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained as a colorless solid (0.025 g, 22%): ¹H NMR(300 MHz, CDCl₃) δ11.59 (br s, 1H), 7.11 (d, J=8.2 Hz, 1H), 7.03-6.87(m, 1H), 4.14-3.77 (m, 6H), 2.94-2.50 (m, 1H), 2.43-1.49 (m, 8H),1.48-1.06 (m, 2H), 1.06-0.75 (m, 3H), 0.75-0.56 (m, 2H); MS (ES+) m/z459.07 (M+1).

Example 387 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((7,7-difluorobicyclo[4.1.0]-heptan-3-yl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-3-yl)methoxy)-2-fluorobenzoicacid and to replace methanesulfonamide with cyclopropanesulfonamide, thetitle compound was obtained as a colorless solid (0.012 g, 11%): ¹H NMR(300 MHz, CDCl₃) δ11.80 (br s, 1H), 7.10 (d, J=8.2 Hz, 1H), 7.02-6.87(m, 1H), 4.14-3.78 (m, 2H), 3.12-2.50 (m, 2H), 2.42-2.05 (m, 2H),2.05-1.27 (m, 5H), 1.28-1.14 (m, 2H), 1.15-0.95 (m, 4H), 0.95-0.74 (m,2H), 0.70-0.54 (m, 2H); MS (ES+) m/z 444.1 (M+1).

Example 388 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-(((1RS,6SR)-7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzamide

Step 1. Preparation of tert-butyl 5-cyclopropyl-4-(((1RS,6SR)-7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoate

Following the procedure as described in Example 342 Step 4 and makingvariations as required to replace tert-butyl4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate withtert-butyl 5-chloro-4-(((1RS,6SR)-7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoate(stereochemistry arbitrarily assigned), the title compound was obtainedas a yellow oil (0.23 g, 81%): MS (ES+) m/z 341.0 (M−55).

Step 2. Preparation of5-cyclopropyl-4-(((1RS,6SR)-7,7-difluorobicyclo[4.1.0]-heptan-1-yl)methoxy)-2-fluorobenzoicacid

Following the procedure as described in Example 332 Step 6, and makingvariations as required to replace tert-butyl4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate withtert-butyl5-cyclopropyl-4-(((1RS,6SR)-7,7-difluorobicyclo[4.1.0]heptan-1-yl)-methoxy)-2-fluorobenzoate,the title compound was obtained as a beige solid (0.12 g, 79%): MS (ES+)m/z 341.0 (M+1).

Step 3. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-(((1RS,6SR)-7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-4-(((1RS,6SR)-7,7-difluorobicyclo-[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoicacid and to replace methanesulfonamide with azetidine-1-sulfonamide, thetitle compound was obtained as a white gum (0.040 g, 30%): ¹H NMR (300MHz, DMSO-d₆) δ 11.61 (br s, 1H), 7.14 (d, J=8.25 Hz, 1H), 6.92 (d,J=12.76 Hz, 1H), 4.17-3.92 (m, 6H), 2.21-2.05 (m, 2H), 2.04-1.54 (m,6H), 1.36-1.14 (m, 4H), 0.92-0.80 (m, 2H), 0.72-0.63 (m, 2H); MS (ES+)m/z 459.1 (M+1).

Example 389 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-4-(((1RS,6SR)-7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith5-cyclopropyl-4-(((1RS,6SR)-7,7-difluorobicyclo-[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoicacid and to replace methanesulfonamide with cyclopropanesulfonamide, thetitle compound was obtained as a white gum (0.030 g, 23%): ¹H NMR (300MHz, DMSO-d₆) δ11.82 (br s, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.92 (d, J=12.9Hz, 1H), 4.17-3.92 (m, 2H), 3.10-2.97 (m, 1H), 2.04-1.54 (m, 6H),1.34-1.15 (m, 4H), 1.14-1.02 (m, 4H), 0.92-0.80 (m, 2H), 0.72-0.62 (m,2H); MS (ES+) m/z 444.1 (M+1).

Example 390 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((2-methylcyclohexyl)methoxy)-benzamide

Step 1. Preparation of tert-butyl5-chloro-2-fluoro-4-((2-methylcyclohexyl)-methoxy)benzoate

To a solution of (2-methylcyclohexyl)methanol (1.28 g, 9.99 mmol) inanhydrous dimethylsulfoxide (20 mL) was added cesium carbonate (5.87 g,18.06 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (2.23 g, 8.96mmol). The reaction mixture was stirred at 70° C. for 16 hours; cooledto ambient temperature and acidified to pH=1 with 5% aqueoushydrochloric acid solution and extracted with ethyl acetate (2×15 mL),the combined organics were washed with brine (15 mL); dried overanhydrous sodium sulfate; filtered and concentrated in vacuo.Purification of the residue by column chromatography (0 to 10% ethylacetate in hexanes) afforded the title compound (2.30 g, 72%); MS (ES+)m/z 303.2, 301.2 (M−54); MS (ES−) m/z 301.2, 299.2 (M−56).

Step 2. Preparation of 5-cyclopropyl-2-fluoro-4-((2-methyl-cyclohexyl)methoxy)benzoic acid

To a solution of tert-butyl5-chloro-2-fluoro-4-((2-methylcyclohexyl)-methoxy)benzoate (1.50 g, 4.30mmol), cyclopropylboronic acid (0.55 g, 6.41 mmol), potassium phosphate(3.60 g, 17.2 mmol) and tricyclohexylphosphine tetrafluoroborate (0.31g, 0.86 mmol) in toluene (15 mL) and water (1.5 mL) under a nitrogenatmosphere was added palladium acetate (0.09 g, 0.43 mmol). The reactionmixture was heated at 130° C. for 30 minutes in the microwave, and thencooled to ambient temperature. Water (20 mL) was added and the mixtureextracted with ethyl acetate, the combined organics were washed withbrine; dried over anhydrous sodium sulfate and concentrated in vacuo.Purification of the residue by column chromatography (5% ethyl acetatein hexanes) afforded tert-butyl5-cyclopropyl-2-fluoro-4-((2-methylcyclohexyl)-methoxy)benzoate (1.5 g,4.3 mmol), which was used directly for the next step. To a solution ofthis compound (1.50 g, 4.30 mmol) in dichloromethane (20 mL) was addedtrifluoroacetic acid (20 mL). The reaction mixture was stirred at 0° C.for 1 hour and then concentrated in vacuo. The residue was triturated indiethyl ether (10 mL), the solid was filtered, rinsed with diethyl ether(2×10 mL) and dried to give the title compound (0.63 g, 48%): ¹H NMR(300 MHz, CDCl₃) δ 7.48 (d, J=8.4 Hz, 1H), 6.58 (d, J=12.9 Hz, 1H), 3.87(dd, J=6.7, 2.3 Hz, 2H), 2.17-1.91 (m, 3H), 1.76-1.31 (m, 8H), 0.98-0.84(m, 5H), 0.67-0.58 (m, 2H).

Step 3. Preparation of5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((2-methylcyclohexyl)methoxy)benzamide

To a stirred solution of5-cyclopropyl-2-fluoro-4-((2-methylcyclohexyl)-methoxy)benzoic acid(0.093 g, 0.305 mmol) in tetrahydrofuran (2 mL) under an atmosphere ofnitrogen was added carbonyldiimidazole (0.074 g, 0.457 mmol) and thereaction mixture was stirred at 70° C. for 1 hour. The mixture wascooled to room temperature and 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.07mL, 0.45 mmol) was added followed by cyclopropanesulfonamide (0.06 mg,0.52 mmol). Stirring was continued at ambient temperature for 18 hours.5% aqueous hydrochloric acid solution (0.15 mL) was added and themixture was concentrated and directly purified by column chromatography(0 to 30% ethyl acetate in hexanes) to afford the title compound (0.05g, 43%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.79-8.58 (m,1H), 7.56 (d, J=9.1 Hz, 1H), 6.57 (d, J=14.5 Hz, 1H), 3.87 (dd, J=7.0,2.7 Hz, 2H), 3.08 (tt, J=8.1, 8.1, 4.8, 4.8 Hz, 1H), 2.21-1.93 (m, 3H),1.76-1.35 (m, 9H), 1.13 (dq, J=6.20, 6.08, 1.31 Hz, 2H), 0.98-0.86 (m,5H), 0.68-0.59 (m, 2H); MS (ES+) m/z 410.1 (M+1); MS (ES−) m/z 408.2(M−1).

Example 391 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((2-methylcyclohexyl)-methoxy)benzamide

Following the procedure as described in Example 390 step 3, and makingvariations as required to replace methanesulfonamide withazetidine-1-sulfonamide, the title compound was obtained (0.034 g, 26%)as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.65 (m, 1H), 7.56 (d,J=9.1 Hz, 1H), 6.58 (d, J=14.4 Hz, 1H), 4.23 (t, J=7.7 Hz, 4H), 3.87(dd, J=6.9, 2.5 Hz, 2H), 2.25 (p, J=7.7 Hz, 2H), 2.17-1.96 (m, 3H),1.77-1.21 (m, 8H), 0.98-0.84 (m, 5H), 0.68-0.60 (m, 2H); MS (ES+) m/z425.1 (M+1); MS (ES−) m/z 423.2 (M−1).

Example 392 Synthesis of5-chloro-N-(cyclopropylsulfonyl)-4-((2,6-dimethylcyclohexyl)-methoxy)-2-fluorobenzamide

Step 1. Preparation of tert-butyl5-chloro-4-((2,6-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate

To a solution of (2,6-dimethylcyclohexyl)methanol (0.34 g, 2.40 mmol) inanhydrous dimethylsulfoxide (5 mL) were added cesium carbonate (1.56 g,4.80 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (0.53 g, 2.16mmol) and the reaction mixture was stirred at 70° C. for 16 hours. Thereaction mixture was cooled down and acidified to pH=1 with 5% aqueoushydrochloric acid solution and extracted with ethyl acetate (2×15 mL),the combined organics were washed with brine (15 mL); dried overanhydrous sodium sulfate, filtered and concentrated in vacuo.Purification of the residue by column chromatography (0 to 10% ethylacetate in hexanes) afforded the title compound (0.43 g, 54%): MS (ES+)m/z 317.2, 315.2 (M−54); MS (ES−) m/z 315.1, 313.1, (M−56).

Step 2. Preparation of5-chloro-4-((2,6-dimethylcyclohexyl)-methoxy)-2-fluorobenzoic acid

To a solution of tert-butyl5-chloro-4-((2,6-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate (0.21 g,0.58 mmol) in dichloromethane (2 mL), was added trifluoroacetic acid (2mL). The reaction mixture was stirred at 0° C. for 1 hour and thenconcentrated in vacuo. The residue was purified by column chromatography(0 to 30% gradient ethyl acetate in hexanes) to afford the titlecompound (0.071 g, 38%): MS (ES−) m/z 315.2, 313.2 (M−1).

Step 3. Preparation of5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((2,6-dimethylcyclohexyl)-methoxy)-2-fluorobenzamide

To a stirred solution of5-chloro-4-((2,6-dimethylcyclohexyl)methoxy)-2-fluorobenzoic acid (0.07g, 0.22 mmol) in tetrahydrofuran (2 mL) under an atmosphere of nitrogenwas added carbonyldiimidazole (0.053 g, 0.33 mmol). The reaction mixturewas stirred at 70° C. for 1 hour. The mixture was cooled to roomtemperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.07 mL, 0.45 mmol)was added followed by cyclopropanesulfonamide (0.045 mg, 0.374 mmol).Stirring continued at room temperature for 18 hours. 5% aqueoushydrochloric acid solution (0.15 mL) was added and the mixture wasconcentrated and directly purified by column chromatography (0 to 30%ethyl acetate in hexanes) to afford the title compound (0.026 g, 28%) asa colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.09-11.90 (m, 1H), 7.71(d, J=7.07 Hz, 1H), 7.35 (d, J=12.32 Hz, 1H), 4.12-4.06 (m, 2H),3.11-2.96 (m, 1H), 1.98-0.80 (m, 19H); MS (ES−) m/z 416.2, 418.2 (M−1).

Example 393 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-4-((2,6-dimethylcyclohexyl)-methoxy)-2-fluorobenzamide

Following the procedure as described in Example 392 step 3, and makingvariations as required to replace methanesulfonamide withazetidine-1-sulfonamide, the title compound was obtained (0.009 g, 10%)as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.73-8.55 (m, 1H), 7.57(d, J=9.1 Hz, 1H), 6.62 (d, J=14.5 Hz, 1H), 4.23 (t, J=7.7 Hz, 4H), 4.01(d, J=4.5 Hz, 2H), 2.34-2.17 (m, 2H), 2.07-1.96 (m, 2H), 1.85-0.58 (m,13H); MS (ES+) m/z 433.1, 435.1 (M+1); MS (ES−) m/z 433.2, 431.2 (M−1).

Example 394 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((2,6-dimethylcyclohexyl)-methoxy)-2-fluorobenzamide

Step 1. Preparation of5-cyclopropyl-4-((2,6-dimethylcyclohexyl)-methoxy)-2-fluorobenzoic acid

To a solution of tert-butyl5-chloro-4-((2,6-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate (0.43 g,1.16 mmol), cyclopropylboronic acid (0.14 g, 1.74 mmol), potassiumphosphate (1.48 g, 7.00 mmol) and tricyclohexylphosphinetetrafluoroborate (0.085 g, 0.230 mmol) in toluene (5 mL) and water (0.5mL) under a nitrogen atmosphere was added palladium acetate (0.04 g,0.12 mmol). The reaction mixture was heated at 130° C. for 30 minutes inthe microwave then cooled to ambient temperature. Water (20 mL) wasadded and the mixture extracted with ethyl acetate (3×10 mL), thecombined organics were washed with brine; dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. Purification of the residueby column chromatography (5% ethyl acetate in hexanes) affordedtert-butyl5-cyclopropyl-4-((2,6-dimethylcyclohexyl)methoxy)-2-fluorobenzoate (0.43g, 1.16 mmol) which was used directly into the next step. To a solutionof this compound (0.43 g, 1.16 mmol) in dichloromethane (2 mL), wasadded trifluoroacetic acid (2 mL). The reaction mixture was stirred at0° C. for 1 hour and then concentrated in vacuo. The residue waspurified by column chromatography (0 to 30% ethyl acetate in hexanes) toafford the title compound (0.142 g, 38%). MS (ES−) m/z 319.2 (M−1).

Step 2. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((2,6-dimethylcyclohexyl)-methoxy)-2-fluorobenzamide

To a stirred solution of5-cyclopropyl-4-((2,6-dimethylcyclohexyl)methoxy)-2-fluorobenzoic acid(0.07 g, 0.22 mmol) in tetrahydrofuran (2 mL) and under an atmosphere ofnitrogen was added carbonyldiimidazole (0.053 g, 0.33 mmol) and thereaction mixture was stirred at 70° C. for 1 hour. The mixture wascooled down to ambient temperature and1,8-diazabicyclo[5.4.0]undec-7-ene (0.07 mL, 0.45 mmol) was addedfollowed by azetidine-1-sulfonamide (0.051 g, 0.37 mmol) and thestirring continued at ambient temperature for 18 hours. 5% aqueoushydrochloric acid solution (0.15 mL) was added and the mixture wasconcentrated and directly purified by column chromatography (0 to 30%ethyl acetate in hexanes) to afford the title compound (0.022 g, 22%) asa colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.75-8.55 (m, 1H), 7.57 (d,J=9.1 Hz, 1H), 6.62 (d, J=14.5 Hz, 1H), 4.23 (t, J=7.7 Hz, 4H), 4.01 (d,J=4.5 Hz, 2H), 2.35-2.17 (m, 2H), 2.07-1.95 (m, 2H), 1.86-0.56 (m, 20H);MS (ES+) m/z 439.1 (M+1); MS (ES−) m/z 437.2 (M−1).

Example 395 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-methylcyclohex-3-en-1-yl)methoxy)benzamide

Step 1. Preparation of tert-butyl 5-chloro-2-fluoro-4-((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methoxy)benzoate

To a solution of (8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methanol (0.301g, 1.65 mmol) in anhydrous dimethylsulfoxide (3 mL) were added cesiumcarbonate (1.07 g, 3.30 mmol) and tert-butyl5-chloro-2,4-difluorobenzoate (0.37 g, 1.49 mmol) and the reactionmixture was stirred at 70° C. for 16 hours. The reaction mixture wascooled down to room temperature and acidified to pH=1 with 5% aqueoushydrochloric acid solution and extracted with diethyl ether (2×15 mL).The combined organic layers were washed with brine (15 mL); dried overanhydrous sodium sulfate, filtered and concentrated in vacuo.Purification of the residue by column chromatography (0 to 10% ethylacetate in hexanes) afforded the title compound (0.28 g, 45%). ¹H NMR(300 MHz, CDCl₃) δ 7.85 (d, J=7.67 Hz, 1H), 6.60 (d, J=12.13 Hz, 1H),3.96-3.89 (m, 4H), 3.72 (s, 1H), 1.98-1.37 (m, 17H), 1.12 (s, 1H).

Step 2. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((1-methyl-4-oxocyclohexyl)-methoxy)benzoate

To a solution of tert-butyl 5-chloro-2-fluoro-4-((8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-methoxy)benzoate (0.28 g, 0.67 mmol),cyclopropylboronic acid (0.08 g, 1.00 mmol), potassium phosphate (0.57g, 2.68 mmol) and tricyclohexylphosphine tetrafluoroborate (0.05 g, 0.14mmol) in toluene (3 mL) and water (0.3 mL) under a nitrogen atmospherewas added palladium acetate (0.016 g, 0.07 mmol). The reaction mixturewas heated at 130° C. for 30 minutes in the microwave and then cooled toambient temperature. Water (20 mL) was added and the mixture extractedwith ethyl acetate (2×15 mL), the combined organics were washed withbrine (10 mL); dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. Purification of the residue by columnchromatography (5% ethyl acetate in hexanes) afforded tert-butyl5-cyclopropyl-2-fluoro-4-((8-methyl-1,4-dioxaspiro[4.5]-decan-8-yl)methoxy)benzoate(0.28 g, 0.67 mmol) which was used directly into the next step. To asolution of this compound (0.28 g, 0.67 mmol) in dichloromethane (5 mL),was added trifluoroacetic acid (0.5 mL). The reaction mixture wasstirred at ambient temperature for 20 minutes and then directly purifiedby column chromatography (0 to 30% ethyl acetate in hexanes) to affordthe title compound (0.071 g, 28%). ¹H NMR (300 MHz, CDCl₃) δ 7.40 (d,J=8.3 Hz, 1H), 6.51 (d, J=12.5 Hz, 1H), 3.85-3.76 (m, 2H), 2.58-2.29 (m,4H), 2.06-1.73 (m, 5H), 1.55 (s, 9H), 1.28 (s, 3H), 0.91-0.82 (m, 2H),0.64-0.57 (m, 2H).

Step 3. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((1-methylcyclohex-3-en-1-yl)-methoxy)benzoate

To a solution of tert-butyl5-cyclopropyl-2-fluoro-4-((1-methyl-4-oxocyclohexyl)-methoxy)benzoate(0.071 g, 0.190 mmol) in (3 mL) and methanol (1 mL) was added sodiumborohydride (0.014 g, 0.38 mmol) and the reaction mixture was stirred 20minutes at ambient temperature. The mixture was then quenched byaddition of 1N hydrochloric acid until reaching pH=1. The mixture wasextracted with dichloromethane (3×10 mL), the organic layers werecombined and washed with brine (15 mL), dried over anhydrous magnesiumsulfate, filtered and concentrated to afford tert-butyl5-cyclopropyl-2-fluoro-4-((4-hydroxy-1-methylcyclohexyl)methoxy)benzoate(0.071 g, 99%) which was used directly for next step. To a solution ofthe previous compound in dichloromethane (3 mL) at −78° C. was addeddropwise diethylaminosulfur trifluoride (0.15 g, 0.94 mmol) dissolved indichloromethane (1 mL) and the reaction mixture was stirred 1 hour at−78° C., then slowly warmed up to ambient temperature during 2 hours.The mixture was then stirred at ambient temperature for a further 1 hourand then cooled down to −78° C. and quenched by addition of methanol (1mL), followed by a saturated aqueous solution of sodium bicarbonate (2mL). The mixture was warmed up to ambient temperature and extracted withdichloromethane (3×10 mL). The organic layers were combined and washedwith brine (15 mL), dried over anhydrous magnesium sulfate, filtered andconcentrated. The residue was purified by chromatography (0 to 30% ethylacetate in hexanes) to give the title compound (0.048 g, 70%). ¹H NMR(300 MHz, CDCl₃) δ 7.38 (d, J=8.43 Hz, 1H), 6.49 (d, J=12.75 Hz, 1H),5.73-5.56 (m, 2H), 3.76-3.61 (m, 2H), 2.14-1.43 (m, 16H), 1.08 (s, 3H),0.92-0.78 (m, 2H), 0.66-0.57 (m, 2H).

Step 4. Preparation of5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-methylcyclohex-3-en-1-yl)methoxy)benzamide

To a solution of tert-butyl5-cyclopropyl-2-fluoro-4-((1-methylcyclohex-3-en-1-yl)methoxy)benzoate(0.041 g, 0.11 mmol) in dichloromethane (2 mL), was addedtrifluoroacetic acid (2 mL). The reaction mixture was stirred at roomtemperature for 1 hour and then concentrated in vacuo to afford5-cyclopropyl-2-fluoro-4-((1-methylcyclohex-3-en-1-yl)methoxy)benzoicacid (0.033 g, 0.11 mmol) which was used directly in the next step. Thiscompound was dissolved in tetrahydrofuran (2 mL) under an atmosphere ofnitrogen and carbonyldiimidazole (0.024 g, 0.15 mmol) was added to thesolution and the reaction mixture was stirred at 70° C. for 1 hour. Themixture was cooled to ambient temperature and1,8-diazabicyclo[5.4.0]undec-7-ene (0.04 mg, 0.17 mmol) was added,followed by cyclopropanesulfonamide (0.021 mg, 0.170 mmol) and stirringcontinued at ambient temperature for 18 hours. 5% aqueous hydrochloricacid solution (0.15 mL) was added and the mixture was concentrated andpurified by column chromatography (0 to 30% ethyl acetate in hexanes) toafford the title compound (0.012 g, 24%) as a colorless solid: ¹H NMR(300 MHz, CDCl₃) δ 9.18-8.28 (br, 1H), 7.60 (s, 1H), 6.56 (d, J=14.4 Hz,1H), 5.75-5.57 (m, 2H), 3.76 (d, J=8.5 Hz, 1H), 3.69 (d, J=8.6 Hz, 1H),3.17-3.00 (m, 1H), 2.18-1.95 (m, 4H), 1.95-1.81 (m, 1H), 1.78-1.63 (m,1H), 1.57-1.36 (m, 3H), 1.23 (s, 3H), 1.18-1.05 (m, 2H), 0.96-0.85 (m,2H), 0.68-0.59 (m, 2H); MS (ES+) m/z 408.2 (M+1); MS (ES−) m/z 406.2(M−1).

Example 396 Synthesis of4-butoxy-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide

Step 1. Preparation of tert-butyl 4-butoxy-5-chloro-2-fluorobenzoate

To a solution of butanol (0.07 g, 0.99 mmol) in anhydrousdimethylsulfoxide (2 mL) were added cesium carbonate (0.59 g, 1.81 mmol)and tert-butyl 5-chloro-2,4-difluorobenzoate (0.22 g, 0.90 mmol) and thereaction mixture was stirred at 70° C. for 16 hours. The reactionmixture was cooled down to room temperature and acidified to pH=1 with5% aqueous hydrochloric acid solution and extracted with ethyl acetate(2×15 mL). The combined organic layers were washed with brine (15 mL);dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.Purification of the residue by column chromatography (0 to 10% ethylacetate in hexanes) afforded the title compound (0.23 g, 72%); MS (ES+)m/z 303.2, 305.2 (M+1).

Step 2. Preparation of 4-butoxy-5-cyclopropyl-2-fluorobenzoic acid

To a solution of tert-butyl 4-butoxy-5-chloro-2-fluorobenzoate (0.23 g,0.76 mmol), cyclopropylboronic acid (0.10 g, 1.14 mmol), potassiumphosphate (0.64 g, 3.10 mmol) and tricyclohexylphosphinetetrafluoroborate (0.05 g, 0.15 mmol) in toluene (3 mL) and water (0.3mL) under a nitrogen atmosphere was added palladium acetate (0.005 g,0.076 mmol). The reaction mixture was heated at 130° C. for 30 minutesin the microwave then cooled to ambient temperature. Water (20 mL) wasadded and the mixture extracted with ethyl acetate (2×15 mL). Thecombined organics were washed with brine; dried over anhydrous sodiumsulfate and concentrated in vacuo. Purification of the residue by columnchromatography (5% ethyl acetate in hexanes) afforded tert-butyl4-butoxy-5-cyclopropyl-2-fluorobenzoate (0.15 g, 67%), which was useddirectly in the next step. To a solution of this compound (0.15 g, 0.48mmol) in dichloromethane (2 mL), was added trifluoroacetic acid (2 mL).The reaction mixture was stirred at room temperature for 1 hour and thenconcentrated in vacuo. The residue was triturated in diethyl ether (10mL) and the solid was filtered, rinsed with diethyl ether (2×10 mL) anddried to give the title compound (0.048 g, 40%). ¹H NMR (300 MHz, CDCl₃)δ 7.48 (d, J=8.3 Hz, 1H), 6.56 (d, J=12.7 Hz, 1H), 4.08-3.95 (m, 2H),2.18-0.39 (m, 14H).

Step 3. Preparation of 4-butoxy-5-cyclopropyl-N-(cyclopropyl-sulfonyl)-2-fluorobenzamide

To a stirred solution of 4-butoxy-5-cyclopropyl-2-fluorobenzoic acid(0.039 g, 0.15 mmol) in tetrahydrofuran (1 mL) and under an atmosphereof nitrogen was added carbonyldiimidazole (0.030 g, 0.18 mmol) and thereaction mixture was stirred at 70° C. for 1 hour. The mixture wascooled down to room temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene(0.02 mL, 0.02 mmol) was added followed by cyclopropanesulfonamide(0.024 g, 0.20 mmol) and the stirring continued at ambient temperaturefor 18 hours. 5% aqueous hydrochloric acid solution (0.15 mL) was addedand the mixture was concentrated and directly purified by columnchromatography (0 to 30% gradient ethyl acetate in hexanes) to affordthe title compound (0.011 g, 20%) as a colorless solid: ¹H NMR (300 MHz,CDCl₃) δ 8.82-8.57 (m, 1H), 7.57 (d, J=9.24 Hz, 1H), 6.58 (d, J=14.42Hz, 1H), 4.04 (t, J=6.30, 6.30 Hz, 2H), 3.16-3.05 (m, 1H), 2.18-1.74 (m,3H), 0.72-0.61 (m, 2H), 1.71-0.84 (m, 13H), 0.74-0.60 (m, 2H); MS (ES+)m/z 356.1 (M+1); MS (ES−) m/z 354.2 (M−1).

Example 397 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-chloro-2,4-difluorobenzamide

Following the procedure as described in Example 332 Step 7 and makingnon-critical variations to replace methanesulfonamide withazetidine-1-sulfonamide and to replace4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidwith 5-chloro-2,4-difluorobenzoic acid, the title compound was obtainedas a colorless powder (7.0 g, 70%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.07(br s, 1H), 7.99 (t, J=7.6 Hz, 1H), 7.71 (t, J=9.8 Hz, 1H), 4.03 (t,J=7.7 Hz, 4H), 2.20-2.10 (m, 2H); MS (ES−) m/z 309.1, 311.1 (M−1).

Example 398 Synthesis of4-((1-((4-chlorophenyl)(phenyl)methyl)azetidin-3-yl)-methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of methyl 5-chloro-2,4-difluorobenzoate

a. To a stirred solution of 5-chloro-2,4-difluorobenzoic acid (10.0 g,52 mmol) in MeOH (150 mL) was added sulfuric acid (1 mL). After stirringat 90° C. for 16 h, the solvent was removed in vacuo and the crudeproduct was quenched by saturated aqueous sodium bicarbonate andextracted with DCM (100 mL×3). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated to give targetcompound (10.0 g, 94%) as a white solid.

Step 2. Preparation of tert-butyl3-((2-chloro-5-fluoro-4-(methoxycarbonyl)-phenoxy)methyl)azetidine-1-carboxylate

A mixture of methyl 5-chloro-2,4-difluorobenzoate (2.2 g, 10.7 mmol),tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (2.0 g, 10.7 mmol)and potassium carbonate (4.43 g, 32.1 mmol) in DMF (30 mL) was stirredat 30° C. for 16 h. The mixture was quenched by water and extracted withEtOAc (50 mL×3). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated. Theresulting residue was purified by silica gel column (eluting withpetroleum ether/ethyl acetate, from 20/1 to 3/1) to give tert-butyl3-((2-chloro-5-fluoro-4-(methoxycarbonyl)phenoxy)methyl)azetidine-1-carboxylate(1.2 g, 30%) as a pale yellow oil. LCMS (ESI) m/z: 318.0 [M-56+H].

Step 3. Preparation of tert-butyl3-((2-cyclopropyl-5-fluoro-4-(methoxycarbonyl)-phenoxy)methyl)azetidine-1-carboxylate

To a mixture of tert-butyl 3-((2-chloro-5-fluoro-4-(methoxycarbonyl)-phenoxy)methyl)-azetidine-1-carboxylate (1.2 g, 3.2 mmol),cyclopropylboronic acid (415 mg, 4.8 mmol), potassium phosphate (2.04 g,9.6 mmol) and tricyclohexylphosphine tetrafluoroborate (118 mg, 0.32mmol) in toluene (20 mL) and water (1 mL) under a nitrogen atmospherewas added palladium acetate (36 mg, 0.16 mmol). The reaction mixture washeated to 100° C. for 16 h and then cooled to ambient temperature. Themixture was quenched by water (50 mL) and extracted with ethyl acetate(50 mL×3), the combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel column (eluting with petroleumether/ethyl acetate, from 10/1 to 2/1) to afford target compound (1.0 g,83%) as a pale yellow solid. LCMS (ESI) m/z: 324.3 [M−56+H]⁺.

Step 4. Preparation of methyl4-(azetidin-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate

A solution of tert-butyl3-((2-cyclopropyl-5-fluoro-4-(methoxycarbonyl)phenoxy)

methyl)azetidine-1-carboxylate (1.0 g, 2.6 mmol) in DCM (5 mL) andtrifluoroacetic acid (5 mL) was stirred at room temperature for 1 h. Thereaction was quenched by saturated aqueous NaHCO₃ and extracted with DCM(30 mL×2). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated to give methyl4-(azetidin-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate (700 mg, crude)as a solid which was used in the next step without purification. LCMS(ESI) m/z: 280.1 [M+H]⁺.

Step 5. Preparation of methyl4-((1-((4-chlorophenyl)(phenyl)-methyl)azetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate

A mixture of methyl4-(azetidin-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate (58 mg, 0.21mmol), 1-chloro-4-(chloro(phenyl)methyl)benzene (74 mg, 0.31 mmol),potassium carbonate (86 mg, 0.62 mmol) and sodium iodide (32 mg, 0.21mmol) in MeCN (10 mL) was stirred at 80° C. for 16 h. The reactionmixture was diluted with EtOAc (100 mL) and brine (50 mL). The organiclayer was separated and washed with brine (50×2 mL), dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by silica gel chromatography (eluting with petroleumether/EtOAc=4/1) to give the target compound (50 mg, 50%) as a paleyellow oil. LCMS (ESI) m/z: 480.1 [M+H].

Step 6. Preparation of4-((1-((4-chlorophenyl)(phenyl)methyl)azetidin-3-yl)-methoxy)-5-cyclopropyl-2-fluorobenzoicacid

A mixture of methyl 4-((1-((4-chlorophenyl)(phenyl)methyl)azetidin3-yl)-methoxy)-5-cyclopropyl-2-fluorobenzoate (50 mg, 0.10 mmol) andlithium hydroxide (13 mg, 0.31 mmol) in THF (10 mL) and H₂O (10 mL) wasstirred at 50° C. for 3 h. The mixture was diluted with EtOAc (100 mL),washed with HCl (2.0 M, 20 mL), brine (50×2 mL), dried over anhydroussodium sulfate, filtered and concentrated to give the target product (50mg) as oil which was used in the next step without further purification.LCMS (ESI) m/z: 466.1 [M+H]⁺.

Step 7. Preparation of4-((1-((4-chlorophenyl)(phenyl)methyl)azetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

A mixture of4-((1-((4-chlorophenyl)(phenyl)methyl)azetidin-3-yl)-methoxy)-5-cyclopropyl-2-fluorobenzoicacid (50 mg, 0.11 mmol), methanesulfonamide (15 mg, 0.16 mmol), EDCI (31mg, 0.16 mmol) and DMAP (20 mg, 0.16 mmol) in DCM (20 mL) was stirred at25° C. for 16 h. The reaction mixture was diluted with EtOAc (100 mL),washed with HCl (2.0 M, 20 mL) and brine (50×2 mL), dried over anhydroussodium sulfate, filtered and concentrated. The residue was purified byreverse phase Combiflash (35%-38% MeCN in 0.5% N_(H)4HCO₃) to give thetarget product (11.0 mg, 19%) as an off-white solid. LCMS (ESI) MethodA: RT=5.83 min, m/z: 543.5 [M+H]⁺. ¹H-NMR (500 MHz, MeOH-d₄): δ7.31-7.29 (m, 4H), 7.23-7.19 (m, 5H), 7.14-7.11 (m, 1H), 6.69-6.66 (m,1H), 4.51 (s, 1H), 4.08 (d, J=6.5 Hz, 2H), 3.39-3.34 (m, 2H), 3.32-3.13(m, 5H), 2.94-2.90 (m, 1H), 1.99-1.96 (m, 1H), 0.84-0.80 (m, 2H),0.58-0.54 (m, 2H).

Example 399 Synthesis of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenyl(3-(trifluoromethoxy)phenyl)methyl)azetidin-3-yl)methoxy)benzamide

Step 1. Preparation of phenyl(3-(trifluoromethoxy)phenyl)methanol

To a solution of 3-(trifluoromethoxy)benzaldehyde (1.30 g, 6.84 mmol) inanhydrous THF (50 mL) was added phenylmagnesium bromide (1.0 M, 17 mL,17 mmol) dropwise at 0° C. The resulting mixture was stirred at 80° C.for 3 h. The mixture was cooled to room temperature and diluted withEtOAc (100 mL). The organic layer was washed with saturated NH₄Cl (50mL) and brine (50×2 mL), dried over anhydrous sodium sulfate, filteredand concentrated. The residue was purified by reverse phase Combiflash(50%-55% MeCN in 0.5% NH₄HCO₃) to give target product (1.36 g, 74%) as apale yellow oil. LCMS (ESI) m/z: 267.1 [M−H]. ¹H-NMR (500 MHz, DMSO-d₆):δ 7.44-7.40 (m, 5H), 7.33-7.30 (m, 2H), 7.23-7.18 (m, 2H), 6.13 (d,J=4.0 Hz, 1H), 5.79 (d, J=4.0 Hz, 1H).

Step 2. Preparation of1-(chloro(phenyl)methyl)-3-(trifluoromethoxy)benzene

A solution of phenyl(3-(trifluoromethoxy)phenyl)methanol (300 mg, 1.12mmol) in thionyl chloride (50 mL) was refluxed for 5 h. The solvent wasremoved and the residue was purified by silica gel chromatography(eluting with petroleum ether/EtOAc=100/1) to give the target compound(140 mg, 44%) as a pale yellow oil. ¹H-NMR (500 MHz, DMSO-d₆): δ7.56-7.49 (m, 5H), 7.42-7.40 (m, 2H), 7.35-7.32 (m, 2H), 6.62 (m, 1H).

Step 3. Preparation of methyl5-cyclopropyl-2-fluoro-4-((1-(phenyl(3-(trifluoromethoxy)-phenyl)methyl)azetidin-3-yl)methoxy)benzoate

The synthetic procedure was similar to step 5 of Example 398. LCMS (ESI)m/z: 530.1 [M+H]⁺.

Step 4. Preparation of5-cyclopropyl-2-fluoro-4-((1-(phenyl(3-(trifluoromethoxy)-phenyl)methyl)azetidin-3-yl)methoxy)benzoicacid

The synthetic procedure was similar to step 6 of Example 398. LCMS (ESI)m/z: 516.0 [M+H]⁺.

Step 5. Preparation of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenyl(3-(trifluoromethoxy)phenyl)methyl)azetidin-3-yl)methoxy)benzamide

The synthetic procedure was similar to step 7 of Example 398. LCMS (ESI)Method A: RT=6.04 min, m/z: 590.8 [M−H]⁻. ¹H-NMR (500 MHz, MeOH-d₄): δ7.33-7.29 (m, 4H), 7.25-7.23 (m, 1H), 7.22-7.20 (m, 3H), 7.15-7.12 (m,1H), 7.04-7.02 (m, 1H), 6.72-6.70 (m, 1H), 4.53 (s, 1H), 4.10 (d, J=6.0Hz, 2H), 3.39-3.31 (m, 2H), 3.17 (s, 3H), 3.15-3.11 (m, 2H), 2.94-2.91(m, 1H), 2.00-1.97 (m, 1H), 0.85-0.81 (m, 2H), 0.58-0.54 (m, 2H).

Example 400 Synthesis of4-((1-((3-chlorophenyl)(phenyl)methyl)azetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of (3-chlorophenyl)(phenyl)methanol

A mixture of methyl (3-chlorophenyl)(phenyl)methanone (1 g, 4.63 mmol)and sodium borohydride (352 mg, 9.26 mmol) in EtOH (6 mL) was stirred at25° C. for 2 h. After removal of the solvent, the mixture was dilutedwith water (20 mL) and extracted with EtOAc (20 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over anhydroussodium sulfate, filtered and concentrated to give the desired product(950 mg, 94%) as yellow oil which was used in the next step withoutfurther purification.

Step 2. Preparation of 1-chloro-3-(chloro(phenyl)methyl)benzene

A solution of (3-chlorophenyl)(phenyl)methanol (500 mg, 2.3 mmol) inthionyl chloride (3 mL) was stirred at 80° C. for 16 h. After cooling toroom temperature, the reaction mixture was concentrated and purified bysilica gel column (eluting with petroleum ether/ethyl acetate=100/1) togive the desired product (200 mg, 37%) as yellow oil.

Step 3. Preparation ofMethyl-4-((1-((3-chlorophenyl)(phenyl)methyl)azetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate

The synthetic procedures were similar to Example 398. LCMS (ESI) m/z:480.1 [M+H]⁺.

Step 4. Preparation of4-((1-((3-chlorophenyl)(phenyl)methyl)azetidin-3-yl)-methoxy)-5-cyclopropyl-2-fluorobenzoicacid

The synthetic procedures were similar to those of Example 398. LCMS(ESI) m/z: 466.1 [M+H]⁺.

Step 5. Preparation of4-((1-((3-chlorophenyl)(phenyl)methyl)azetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

The synthetic procedures were similar to those of Example 398. LCMS(ESI) Method A: RT=5.77 min, m/z: 543.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): δ 7.47-7.40 (m, 4H), 7.32-7.18 (m, 7H), 6.86 (d, J=10.0 Hz,1H), 4.50 (s, 1H), 4.18 (d, J=6.5 Hz, 2H), 3.27-3.23 (m, 2H), 3.08 (s,3H), 3.02-2.99 (m, 2H), 2.87-2.85 (m, 1H), 2.08-2.04 (m, 1H), 0.91-0.87(m, 2H), 0.62-0.61 (m, 2H).

Example 401 Synthesis of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenyl(4-(trifluoromethoxy)phenyl)methyl)azetidin-3-yl)methoxy)benzamide

The synthetic procedures were similar to those of Example 399. LCMS(ESI) Method A: RT=4.69 min, m/z: 593.2 [M+H]⁺. ¹H NMR (500 MHz, MeOD):δ 7.54-7.52 (m, 2H), 7.43-7.41 (m, 3H), 7.33-7.30 (m, 3H), 7.24-7.21 (m,2H), 6.72-6.69 (m, 1H), 4.56 (s, 1H), 4.16 (d, J=6.0 Hz, 2H), 3.44-3.38(m, 2H), 3.20-3.16 (m, 2H), 3.10 (s, 3H), 3.02-2.97 (m, 1H), 2.11-2.06(m, 1H), 0.92-0.89 (m, 2H), 0.67-0.66 (m, 2H).

Example 402 Synthesis of4-((1-benzhydrylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of (1-benzhydrylpiperidin-4-yl)methanol

To a solution of (bromomethylene)dibenzene (115 mg, 1.0 mmol) andpiperidin-4-ylmethanol (247 mg, 1.0 mmol) in DMF (5 mL) was addedpotassium carbonate (276 mg, 2.0 mmol), and the reaction mixture wasstirred at 100° C. for 16 h. After cooling to room temperature, themixture was quenched with water (50 mL) and extracted with ethyl acetate(10 mL×3). The combined organic layers were washed with brine (20 mL),dried over anhydrous sodium sulfate, filtered, and concentrated. Theresidue was purified by silica column chromatography (eluting withpetroleum ether/ethyl acetate=3/1) to give(1-benzhydrylpiperidin-4-yl)methanol (280 mg, 99% yield) as white solid.LCMS (ESI) m/z: 281.9 [M+H]⁺.

Step 2. Preparation of4-((1-benzhydrylpiperidin-4-yl)methoxy)-5-chloro-2-fluorobenzoic acid

A mixture of (1-benzhydrylpiperidin-4-yl)methanol (370 mg, 1.3 mmol),tert-butyl 5-chloro-2,4-difluorobenzoate (328 mg, 1.3 mmol) andpotassium tert-butanolate (295 mg, 2.6 mmol) in DMSO (4 mL) was stirredat room temperature for 16 h. The reaction mixture was quenched by water(50 mL) and extracted with ethyl acetate (10 mL×4). The combined organiclayers were washed with brine (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was washed with ethylacetate (5 mL) and filtered to afford4-((1-benzhydrylpiperidin-4-yl)methoxy)-5-chloro-2-fluorobenzoic acid(480 mg, 82%) as a white solid. LCMS (ESI) m/z: 454.2 [M+H]⁺.

Step 3. Preparation of 4-((1-benzhydrylpiperidin-4-yl)methoxy)5-cyclopropyl-2-fluorobenzoic acid

A mixture of4-((1-benzhydrylpiperidin-4-yl)methoxy)-5-chloro-2-fluorobenzoic acid(480 mg, 0.94 mmol), cyclopropylboronic acid (162 mg, 1.88 mmol),potassium phosphate (797 mg, 3.67 mmol), palladium acetate (21 mg, 0.047mmol) and tricyclohexylphosphine tetrafluoroborate (36 mg, 0.094 mmol)in toluene (10 mL) and water (0.5 mL) was stirred under a nitrogenatmosphere at 100° C. for 18 h. The reaction mixture was cooled down,quenched with water (50 mL) and extracted with ethyl acetate (20 mL×3).The combined organic layers were washed with brine (20 mL), dried overanhydrous sodium sulfate, filtered and concentrated to afford product(320 mg, 46%, crude) as oil which was used in the next step withoutfurther purification. LCMS (ESI) m/z: 458.1 [M+H]⁺.

Step 4. Preparation of4-((1-benzhydrylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

A solution of4-((1-benzhydrylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid (270 mg, 0.59 mmol), methanesulfonamide (84 mg, 0.88 mmol), EDCI(169 mg, 0.88 mmol) and DMAP (107 mg, 0.88 mmol) in DCM (5 mL) wasstirred at room temperature for 16 h. The reaction was quenched withwater (5 mL) then adjusted pH to 1 with HCl (1 M). The resulting mixturewas extracted with DCM (5 mL×3), dried over anhydrous sodium sulfate,filtered and concentrated. The resulting residue was purified by reversephase Combiflash (20%-50% CH₃CN/H₂O in 0.1% NH₄HCO₃) to afford thetarget compound (15 mg, 5%) as a white solid. LCMS (ESI) Method A:RT=6.10 min, m/z: 537.2 [M+H]⁺. ¹H-NMR (500 MHz, MeOD-d₄,): δ 7.40-7.42(m, 4H), 7.15-7.30 (m, 7H), 6.67 (d, J=13 Hz, 1H), 4.30 (s, 1H), 3.87(d, J=6 Hz, 2H), 2.82 (s, 3H), 1.73-1.98 (m, 7H), 1.37-1.40 (m, 3H),0.83-0.86 (m, 2H), 0.50-0.53 (m, 2H).

Example 403 Synthesis of4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of methyl4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-2-fluoro-5-iodobenzoate

A mixture of 2-(5-fluoro-2-iodo-4-(methoxycarbonyl)phenyl)acetic acid(100 mg, 0.30 mmol), 1-benzhydrylpiperazine (82 mg, 0.33 mmol),1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45mmol), 1H-benzo[d][1,2,3]triazol-4-ol (61 mg, 0.45 mmol) andtriethylamine (91 mg, 0.90 mmol) in DCM (5.0 mL) was stirred at roomtemperature for 16 h. The mixture was diluted with DCM (20 mL), washedwith HCl (2M, 10 mL) and brine (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified byCombiflash (60%-70% CH₃CN in 0.1% HCOOH) to afford methyl4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-2-fluoro-5-iodobenzoate(70 mg, 41%) as a white solid. LCMS (ESI): m/z: 572.8 [M+H]⁺.

Step 2. Preparation of methyl4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-5-cyclopropyl-2-fluorobenzoate

To a solution of methyl4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-2-fluoro-5-iodobenzoate(70 mg, 0.12 mmol), cyclopropylboronic acid (16 mg, 0.18 mmol),potassium phosphate (102 mg, 0.48 mmol) and tricyclohexylphosphinetetrafluoroborate (9 mg, 0.024 mmol) in toluene (2 mL) and water (0.1mL) under a nitrogen atmosphere was added palladium acetate (8 mg, 0.037mmol). The reaction mixture was heated to 100° C. for 18 hours thencooled to ambient temperature. The reaction mixture was quenched withwater (10 mL), extracted with ethyl acetate (10 mL×3). The combinedorganic layers were washed with brine (10 mL), dried over anhydroussodium sulfate, filtered and concentrated to afford the target compound(70 mg, crude) which was used in the next step without purification.LCMS (ESI): m/z: 486.9 [M+H]⁺.

Step 3. Preparation of4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-5-cyclopropyl-2-fluorobenzoicacid

To a solution of methyl4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-5-cyclopropyl-2-fluorobenzoate(70 mg, 0.14 mmol) in THF (2 mL) and methanol (2 mL), lithium hydroxide(2M, 2 mL) was added. After stirring at room temperature for 16 h, themixture pH was adjusted to 2-3 with HCl (2 M) and extracted by ethylacetate (10 mL×3). The combined organic layers were washed with brine(10 mL), dried over anhydrous sodium sulfate, filtered and concentrated.The residue was purified by Combiflash (30%-40% CH₃CN in 0.1% HCOOH) toafford target compound (35 mg, 53%) as a white solid. LCMS (ESI): m/z:473.2 [M+H]⁺.

Step 4. Preparation of4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

A mixture of4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-5-cyclopropyl-2-fluorobenzoicacid (35 mg, 0.074 mmol), methanesulfonamide (11 mg, 0.11 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.15mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol) in dichloromethane(2 mL) was stirred at room temperature for 16 h. The mixture was dilutedwith DCM (10 mL), washed with HCl (2M, 8 mL) and brine (8 mL), driedover anhydrous sodium sulfate, filtered and concentrated. The residuewas purified by Combiflash (30%-40% CH₃CN in 0.1% NH₄HCO₃) to affordtarget compound (5 mg, 12.3%) as a white solid. LCMS (ESI) Method A:RT=5.17 min, m/z: 550.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): δ 7.44-7.43(m, 4H), 7.31-7.26 (m, 5H), 7.21-7.18 (m, 2H), 6.82 (d, J=11.0 Hz, 1H),4.34 (s, 1H), 3.81 (s, 2H), 3.53 (brs, 4H), 2.88 (s, 3H), 2.28 (brs,4H), 1.76-1.75 (m, 1H), 0.83-0.81 (m, 2H), 0.51-0.49 (m, 2H).

Example 404 Synthesis of4-((1-benzoylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of methyl4-((1-benzoylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate

To a mixture of methyl4-(azetidin-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate (50 mg, 0.18mmol), benzoyl chloride (28 mg, 0.20 mmol), and triethylamine (36 mg,0.36 mmol) in DCM (10 mL) was stirred at 20° C. for 1 hour. The mixturewas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated to get a crude product (70 mg, 99%) which was used in thenext step without further purification. LCMS (ESI) m/z: 384.1 [M+H]⁺.

Step 2. Preparation of4-((1-benzoylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid

A mixture of methyl4-((1-benzoylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate (70mg, 0.18 mmol) and lithium hydroxide (22 mg, 0.91 mmol) in THF (5 mL)and H₂O (10 ml) was stirred at room temperature for 18 h. The mixturewas quenched with HCl (1N, 2 mL) and extracted with ethyl acetate (10mL×3). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated to get the targetcompound (50 mg, 74%) as a yellow solid. LCMS (ESI) m/z: 370.1 [M+H].

Step 3. Preparation of4-((1-benzoylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

A mixture of4-((1-benzoylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid(20 mg, 0.05 mmol), EDCI (21 mg, 0.10 mmol), DMAP (12 mg, 0.10 mmol) andmethanesulfonamide (9 mg, 0.10 mmol) in DCM (5 mL) was stirred at roomtemperature for 18 h. The mixture was diluted with DCM (10 mL) andwashed with HCl (2 N, 15 mL×2). The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by HPLC (20%-30% CH₃CN in 0.1% NH₄HCO₃) to give target compound(4 mg, 17%) as a pale yellow solid. LCMS (ESI) Method A: RT=3.86 min,m/z: 446.5 [M+H]⁺. ¹H-NMR (500 MHz, MeOH-d₄,): δ 7.67-7.31 (m, 5H), 7.30(d, J=8.5 Hz, 1H), 6.89 (d, J=13.0 Hz, 1H), 4.65-3.62 (m, 1H), 4.61-4.22(m, 5H), 3.36 (s, 3H), 3.25-3.23 (m, 1H), 1.99-1.95 (m, 1H), 0.94-0.61(m, 4H).

Example 405 Synthesis of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenylsulfonyl)azetidin-3-yl)methoxy)benzamide

The synthetic procedure was same as Example 404. LCMS (ESI) Method A:RT=4.26 min, m/z: 483.2 [M+H]⁺. ¹H-NMR (500 MHz, MeOH-d₄,): δ 7.90-7.66(m, 5H), 7.26 (d, J=8.0 Hz, 1H), 6.76 (d, J=12.5 Hz, 1H), 4.02 (d, J=5.5Hz, 1H), 3.98-3.80 (m, 5H), 3.36 (s, 3H), 2.99-2.96 (m, 1H), 1.91-1.88(m, 1H), 0.91-0.88 (m, 2H), 0.63-0.60 (m, 2H).

Example 406 Synthesis of4-(1-benzhydrylazetidin-3-yloxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of tert-butyl4-(1-benzhydrylazetidin-3-yloxy)-5-chloro-2-fluorobenzoate

A mixture of 1-benzhydrylazetidin-3-ol (500 mg, 2.08 mmol), tert-butyl5-chloro-2,4-difluorobenzoate (568 mg, 2.29 mmol) and potassiumtert-butoxide (349 mg, 3.12 mmol) in DMSO (30 mL) was stirred at 20° C.for 1 h. The mixture was quenched with water and extracted with EtOAc(30 mL×3). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated to get thetarget compound (700 mg, 72%) which was used in the next step withoutfurther purification. LCMS (ESI) m/z: 468.2 [M+H]⁺.

Step 2. Preparation of tert-butyl4-(1-benzhydrylazetidin-3-yloxy)-5-cyclopropyl-2-fluorobenzoate

A mixture of tert-butyl4-(1-benzhydrylazetidin-3-yloxy)-5-chloro-2-fluorobenzoate (700 mg, 1.50mmol), cyclopropylboronic acid (258 mg, 3.00 mmol),tricyclohexylphosphine tetrafluoroborate (57 mg, 0.15 mmol), potassiumphosphate (954 mg, 4.5 mmol) and palladium acetate (224 mg, 0.15 mmol)in toluene (20 mL) and H₂O (1 mL) was stirred at 100° C. for 18 h. Themixture was filtered and diluted with ethyl acetate, washed with brineand concentrated. The residue was purified by silica gel chromatography(eluting with ethyl acetate/ petroleum ether from 0/10 to 1/10) to givetarget product (650 mg, 92%) as a yellow oil. LCMS (ESI) m/z: 474.2[M+H].

Step 3. Preparation of4-(1-benzhydrylazetidin-3-yloxy)-5-cyclopropyl-2-fluorobenzoic acid

A solution of tert-butyl4-(1-benzhydrylazetidin-3-yloxy)-5-cyclopropyl-2-fluorobenzoate (650 mg,1.37 mmol) in DCM (10 mL) and trifluoroacetic acid (5 mL) was stirred atroom temperature for 2 h. The solvent was removed and the residue wasused in the next step without further purification.

Step 4. Preparation of4-(1-benzhydrylazetidin-3-yloxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

A mixture of4-(1-benzhydrylazetidin-3-yloxy)-5-cyclopropyl-2-fluorobenzoic acid (100mg, 0.24 mmol), EDCI (69 mg, 0.36 mmol), DMAP (44 mg, 0.36 mmol) andmethanesulfonamide (34 mg, 0.36 mmol) in DCM (15 mL) was stirred at roomtemperature for 18 h. The mixture was diluted with DCM (10 mL) andwashed with HCl (2 N, 15 mL×2). The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by Combiflash (20%-50% CH₃CN/H₂O in 0.1% NH₄HCO₃) to givetarget compound (40 mg, 34%) as a pale yellow solid. LCMS (ESI) MethodA: RT=5.29 min, m/z: 495.1 [M+H]⁺. ¹H-NMR (500 MHz, MeOH-d₄,): δ7.54-7.46 (m, 10H), 7.29 (d, J=8.0 Hz, 1H), 6.64 (d, J=12.0 Hz, 1H),5.83 (s, 1H), 5.29-5.26 (m, 1H), 4.75-4.71 (m, 2H), 4.41-4.38 (m, 2H),3.37 (s, 3H), 2.22-2.18 (m, 1H), 1.03-0.99 (m, 2H), 0.75-0.42 (m, 2H).

Example 407 Synthesis of4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of4-((1-benzhydrylazetidin-3-yl)methoxy)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

To a solution of (1-benzhydrylazetidin-3-yl)methanol (40.4 mg, 0.159mmol) and 5-chloro-2,4-difluoro-N-methylsulfonyl-benzamide (43.0 mg,0.159 mmol) in DMSO (0.80 mL) at rt was added potassium tert-butoxide in1:10 THF-DMSO (0.38 mL, 0.93 M). The mixture was stirred at rt for 1 hr.LCMS showed major product. Diluted with EtOAc, the contents were washedwith 1:4 mixture of 1M HCl and 1M NaH₂PO₄ (2×) and brine (1×), dried(Na₂SO₄). After filtration and concentration, the crude was purifiedwith HPLC (55.7 mg).

Step 2. Preparation of4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide

A mixture of product from step 1 (29.1 mg), cyclopropylboronic acid(31.4 mg), potassium phosphate (188 mg), palladium acetate (2.8 mg) andtricyclohexylphosphine tetrafluoroborate (8.8 mg) in toluene (1.2 mL)and water (0.06 mL) was heated at 95° C. for 16 hours. The contents wereconcentrated. The residue was diluted with EtOAc and washed with 1MNaH₂PO₄ and brine, and dried (Na₂SO₄). After filtration andconcentration, the crude was purified with HPLC (10.3 mg). LCMS (MethodD): RT=5.44 min, m/z: 509.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.78(s, 1H), 7.46-7.38 (m, 4H), 7.29 (t, J=7.5 Hz, 4H), 7.18 (dd, J=18.0,7.9 Hz, 3H), 6.96 (d, J=12.9 Hz, 1H), 4.54 (s, 1H), 4.22 (d, J=6.2 Hz,2H), 3.07 (s, 2H), 2.89 (s, 1H), 2.13-1.98 (m, 1H), 0.96-0.83 (m, 2H),0.72-0.61 (m, 2H).

Example 408 Synthesis of4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-N-(ethylsulfonyl)-2-fluorobenzamide

Step 1. Preparation of tert-butyl4-((1-benzhydrylazetidin-3-yl)methoxy)-5-chloro-2-fluorobenzoate

To solution of (1-benzhydrylazetidin-3-yl)methanol (368 mg) andtert-butyl 5-chloro-2,4-difluoro-benzoate (397 mg) in DMSO (7.3 mL) at14° C. (bath) was added potassium tert-butoxide (196 mg). The mixturewas stirred at rt for 1 hr. Diluted with EtOAc, the contents were washedwith 1:4 mixture of 1M HCl and 1M NaH₂PO₄ (2×) and brine (1×), dried(Na₂SO₄). After filtration and concentration, the crude was purifiedwith flash chromatography (0-40% EtOAc/heptane) to give the product (511mg).

Step 2. Preparation of tert-butyl4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate

A mixture of tert-butyl4-((1-benzhydrylazetidin-3-yl)methoxy)-5-chloro-2-fluorobenzoate (500mg), cyclopropylboronic acid (188 mg), potassium phosphate (1.12 g) intoluene (6.2 mL) and water (0.31 mL) was purge with nitrogen.Tricyclohexylphosphine tetrafluoroborate (79 mg) and palladium acetate(24 mg) were added. The mixture was heated at 90° C. for 16 hours. Themixture was diluted with EtOAc and filtered. The filtrate wasconcentrated. The residue was purified with flash chromatography (0-30%EtOAc/heptane) to give the product (276 mg).

Step 3. Preparation of4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid

A mixture of tert-butyl4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate(203 mg) and potassium hydroxide (187 mg) in DMSO (1.7 mL) was stirredat rt for 16 hr. The contents were acidified with 1M NaH₂PO₄. Solid wascollected with filtration, washed with water, and dried under vacuum(171 mg).

Step 4. Preparation of4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-N-(ethylsulfonyl)-2-fluorobenzamide

A mixture of4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid (35.6 mg), ethanesulfonamide (22.5 mg), HBTU (41.9 mg), and DIPEA(0.073 mL) in DCE (0.83 mL) was heated at 35° C. for 16 hr then at 55°C. for 1 hr. More ethyanesulfonamide (9 mg) was added. Heating continuedfor 1 hr. Added with 1M NaH₂PO₄, the contents were extracted with DCM(2×). The combined extracts were dried (Na₂SO₄). The crude was purifiedwith HPLC (23 mg). LCMS (Method D): RT=5.08 min, m/z: 523.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 11.78 (s, 1H), 7.49-7.36 (m, 4H), 7.28 (dd,J=8.3, 6.8 Hz, 4H), 7.22-7.09 (m, 3H), 6.95 (d, J=12.8 Hz, 1H), 4.49 (s,1H), 4.21 (d, J=6.2 Hz, 2H), 3.47-3.36 (m, 2H), 3.02 (s, 2H), 2.93-2.81(m, 1H), 2.10-1.99 (m, 1H), 1.22 (t, J=7.5 Hz, 3H), 0.95-0.82 (m, 2H),0.71-0.61 (m, 2H).

Example 409 Synthesis of4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide

The compound was prepared in a similar manner to Example 408 from4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and cyclopropanesulfonamide. LCMS (Method D): RT=4.69 min, m/z:535.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.75 (s, 1H), 7.48-7.36 (m,4H), 7.28 (t, J=7.4 Hz, 4H), 7.23-7.09 (m, 3H), 6.96 (d, J=12.8 Hz, 1H),4.50 (s, 1H), 4.22 (d, J=6.1 Hz, 2H), 3.12-2.96 (m, 3H), 2.94-2.80 (m,1H), 2.12-1.99 (m, 1H), 1.18-0.97 (m, 4H), 0.95-0.82 (m, 2H), 0.73-0.60(m, 2H).

Example 410 Synthesis ofN-(azetidin-1-ylsulfonyl)-4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzamide

The compound was prepared in a similar manner to Example 408 from4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and azetidine-1-sulfonamide. LCMS (Method D): RT=4.74 min, m/z:550.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.57 (s, 1H), 7.46-7.38 (m,4H), 7.28 (dd, J=8.3, 6.8 Hz, 4H), 7.22-7.13 (m, 3H), 6.99-6.87 (m, 1H),4.46 (s, 1H), 4.21 (d, J=6.1 Hz, 2H), 3.97 (s, 3H), 3.28-3.21 (m, 2H),3.07-2.94 (m, 2H), 2.91-2.81 (m, 1H), 2.20-1.99 (m, 3H), 1.25 (d, J=6.9Hz, 1H), 0.93-0.85 (m, 2H), 0.70-0.62 (m, 2H).

Example 411 Synthesis of4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(N-methylsulfamoyl)benzamide

The compound was prepared in a similar manner to Example 408 from4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and N-methylsulfamide. LCMS (Method D): RT=4.48 min, m/z: 524.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.46 (s, 1H), 7.46-7.38 (m, 4H),7.27 (t, J=7.7 Hz, 4H), 7.22-7.08 (m, 3H), 6.95 (d, J=12.7 Hz, 1H), 4.46(s, 1H), 4.21 (d, J=6.2 Hz, 2H), 3.24 (d, J=7.4 Hz, 2H), 3.00 (t, J=6.6Hz, 2H), 2.92-2.79 (m, 1H), 2.53 (d, J=4.9 Hz, 2H), 2.11-1.99 (m, 1H),1.25 (d, J=7.1 Hz, 1H), 0.93-0.83 (m, 2H), 0.67 (m, 2H).

Example 412 Synthesis of5-chloro-4-(cyclohex-3-en-1-ylmethoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of5-chloro-4-(cyclohex-3-en-1-ylmethoxy)-2-fluorobenzoic acid

To a solution of cyclohex-3-en-1-ylmethanol (1.00 g) and5-chloro-2,4-difluoro-benzoic acid (1.72 g) in DMSO (36 mL) at 14° C.(bath) was added potassium tert-butoxide (2.20 g) gradually. The mixturewas stirred at that temp for 5 min then at rt for 30 min. Diluted withEtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1MNaH₂PO₄ (3×) and brine, and dried (Na₂SO₄). After filtration andconcentration, the product was obtained as white solid (2.48 g).

Step 2. Preparation of5-chloro-4-(cyclohex-3-en-1-ylmethoxy)-2-fluoro-N-(methylsulfonyl)benzamide

A mixture of 5-chloro-4-(cyclohex-3-en-1-ylmethoxy)-2-fluorobenzoic acid(53 mg), methanesulfonamide (35 mg), HBTU (95 mg), and DIPEA (0.13 mL)in dichloromethane (0.83 mL) was stirred at rt for 4 hr. Diluted withEtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1MNaH₂PO₄ (2×) and brine, and dried (Na₂SO₄). The crude was purified withHPLC. LCMS (Method D): RT=5.62 min, m/z: 362.1 [M+H]. ¹H NMR (400 MHz,DMSO-d₆) δ 12.07 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.4 Hz,1H), 5.69 (d, J=2.1 Hz, 2H), 4.06 (dd, J=6.5, 1.3 Hz, 2H), 2.28-1.97 (m,4H), 1.98-1.76 (m, 2H), 1.50-1.29 (m, 1H).

Example 413 Synthesis of4-(adamantan-1-ylmethoxy)-3-chloro-2,5-difluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of4-(adamantan-1-ylmethoxy)-3-chloro-2,5-difluorobenzoic acid

To a solution of 1-adamantylmethanol (309 mg) and3-chloro-2,4,5-trifluoro-benzoic acid (391 mg) in DMSO (5.6 mL) at 14°C. (bath) was added potassium tert-butoxide (458 mg) gradually. Themixture was stirred at that temp for 30 min. Diluted with EtOAc, thecontents were washed with 1:4 mixture of 1M HCl and 1M NaH₂PO₄ (3×) andbrine, and dried (Na₂SO₄). After filtration and concentration, theproduct was obtained as white solid (1.00 g).

Step 2:4-(adamantan-1-ylmethoxy)-3-chloro-2,5-difluoro-N-(methylsulfonyl)benzamide

The compound was prepared in a similar manner to step 2 of Example 412from 4-(adamantan-1-ylmethoxy)-3-chloro-2,5-difluorobenzoic acid andmethanesulfonamide. LCMS (Method D): RT=6.97 min, m/z: 434.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 7.66 (dd, J=11.6, 6.6 Hz, 1H), 3.82 (d, J=2.0Hz, 2H), 1.99 (s, 3H), 1.82-1.56 (m, 12H).

Example 414 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-3-chloro-2,5-difluorobenzamide

The compound was prepared in a similar manner to step 2 of Example 412from 4-(adamantan-1-ylmethoxy)-3-chloro-2,5-difluorobenzoic acid andazetidine-1-sulfonamide. LCMS (Method D): RT=7.35 min, m/z: 475.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.60 (dd, J=11.7, 6.6 Hz, 1H), 3.86(t, J=7.6 Hz, 4H), 3.77 (d, J=1.7 Hz, 2H), 2.08 (p, J=7.6 Hz, 2H),2.02-1.93 (m, 3H), 1.77-1.59 (m, 12H).

Example 415 b. Synthesis of4-(adamantan-1-ylmethoxy)-3-chloro-5-fluoro-N-(methylsulfonyl)benzamide

The compound was prepared in a similar manner to Example 413 from3-chloro-4,5-difluorobenzoic acid. LCMS (Method D): RT=7.24 min, m/z:416.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.84-7.77 (m, 1H), 7.68 (dd,J=12.1, 2.0 Hz, 1H), 3.70 (d, J=1.5 Hz, 2H), 2.96 (s, 3H), 1.99 (t,J=3.3 Hz, 3H), 1.79-1.59 (m, 12H).

Example 416 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-3-chloro-5-fluorobenzamide

The compound was prepared in a similar manner to Example 414 from3-chloro-4,5-difluorobenzoic acid. LCMS (Method D): RT=7.87 min, m/z:457.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (t, J=1.7 Hz, 1H), 7.74(dd, J=12.1, 2.1 Hz, 1H), 3.83 (t, J=7.6 Hz, 4H), 3.71 (d, J=1.5 Hz,2H), 2.13-1.94 (m, 5H), 1.79-1.59 (m, 12H).

Example 417 Synthesis of4-(adamantan-1-ylmethoxy)-5-chloro-2,3-difluoro-N-(methylsulfonyl)benzamide

The compound was prepared in a similar manner to Example 413 from5-chloro-2,3,4-trifluorobenzoic acid. LCMS (Method D): RT=7.00 min, m/z:434.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (dd, J=7.2, 2.4 Hz, 1H),3.74 (d, J=1.5 Hz, 2H), 2.86 (s, 3H), 1.98 (q, J=3.1 Hz, 3H), 1.77-1.58(m, 12H).

Example 418 Synthesis of4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-chloro-2,3-difluorobenzamide

The compound was prepared in a similar manner to Example 414 from5-chloro-2,3,4-trifluorobenzoic acid. LCMS (Method D): RT=7.89 min, m/z:475.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.61 (dd, J=7.0, 2.4 Hz, 1H),3.89-3.69 (m, 6H), 2.10-1.93 (m, 5H), 1.76-1.59 (m, 12H).

Example 419 Synthesis of5-chloro-4-((3,3-difluorocyclohexyl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of tert-butyl5-chloro-2-fluoro-4-((3-oxocyclohexyl)-methoxy)benzoate

To a solution of 3-(hydroxymethyl)cyclohexanone (575 mg) and tert-butyl5-chloro-2,4-difluoro-benzoate (1.23 g) in DMSO (13.5 mL) at 14° C.(bath) was added potassium tert-butoxide (604 mg) gradually. After 5min, the mixture was stirred at rt for 30 min. Diluted with EtOAc, thecontents were washed with dilute NaHCO₃ (3×) and brine, and dried(Na₂SO₄). After filtration and concentration, the crude was purifiedwith flash chromatography (0->40% EtOAc/heptane) to give the product(445 mg).

Step 2. Preparation of tert-butyl5-chloro-4-((3,3-difluorocyclohexyl)-methoxy)-2-fluorobenzoate

To a solution tert-butyl5-chloro-2-fluoro-4-((3-oxocyclohexyl)methoxy)benzoate

(384 mg) in dichloromethane (6.5 mL) at 0° C. (bath) was addedbis(2-methoxyethyl)aminosulfur trifluoride (0.63 mL). The mixture wasstirred at rt for 18 hr. Diluted with EtOAc, the contents were washedwith diluted NaHCO₃ and dried (Na₂SO₄). The crude was purified withflash chromatography (0->20% EtOAc/heptane) to give the product (212mg).

Step 3. Preparation of5-chloro-4-((3,3-difluorocyclohexyl)methoxy)-2-fluorobenzoic acid

A solution of tert-butyl 5-chloro-4-((3,3-difluorocyclohexyl)methoxy)-2-fluorobenzoate (64.4 mg) in dichloromethane (0.34 mL) andtrifluoroacetic acid (0.17 mL) was stirred at 0° C. for 10 min then atrt for 2 h. The contents were concentrated. The residue was re-dissolvedwith dichloromethane and concentrated. The crude was dried under vacuumand used directly.

Step 4. Preparation of5-chloro-4-((3,3-difluorocyclohexyl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

A mixture of the product from step 3, methanesulfonamide (32 mg), HBTU(86 mg), and DIPEA (0.18 mL) in dichloromethane (1.7 mL) was stirred atrt for 16 hr. Diluted with EtOAc, the contents were washed with 1:4mixture of 1M HCl and 1M NaH₂PO₄ (2×) and brine, and dried (Na₂SO₄). Thecrude was purified with HPLC. LCMS (Method D): RT=5.35 min, m/z: 400.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 1H), 7.78 (d, J=7.7 Hz,1H), 7.14 (d, J=12.3 Hz, 1H), 4.13-3.98 (m, 2H), 3.13 (s, 3H), 2.18 (s,1H), 2.04 (s, 2H), 1.90-1.56 (m, 4H), 1.55-1.39 (m, 1H), 1.19 (m, 1H).

Example 420 Synthesis of5-cyclopropyl-4-((3,3-difluorocyclohexyl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

Step 1. Preparation of tert-butyl5-cyclopropyl-4-((3,3-difluorocyclohexyl)-methoxy)-2-fluorobenzoate

The compound was prepared in a similar manner to step 2 of Example 419from tert-butyl5-chloro-4-((3,3-difluorocyclohexyl)methoxy)-2-fluorobenzoate.

Step 2. Preparation of5-cyclopropyl-4-((3,3-difluorocyclohexyl)methoxy)-2-fluorobenzoic acid

A solution of tert-butyl5-cyclopropyl-4-((3,3-difluorocyclohexyl)methoxy)-2-fluorobenzoate (191mg) in dichloromethane (1.0 mL) and trifluoroacetic acid (0.5 mL) wasstirred at 0° C. for 30 min then at rt for 3 h. The contents wereconcentrated. The residue was suspended in toluene and concentrated. Thebeige solid was dried under vacuum (162 mg).

Step 3. Preparation of5-cyclopropyl-4-((3,3-difluorocyclohexyl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide

The compound was prepared in a similar manner to step 4 of Example 419from 5-cyclopropyl-4-((3,3-difluorocyclohexyl)methoxy)-2-fluorobenzoicacid. Two enantiomers were separated with chiral chromatography.Enantiomer 1: LCMS (Method D): RT=5.81 min, m/z: 406.1 [M+H]. ¹H NMR(400 MHz, DMSO-d₆) δ 11.85 (s, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.91 (d,J=13.0 Hz, 1H), 4.08-3.92 (m, 2H), 3.25 (s, 3H), 2.20 (s, 1H), 2.14-1.95(m, 3H), 1.89-1.60 (m, 4H), 1.56-1.40 (m, 1H), 1.30-1.14 (m, 1H),0.95-0.84 (m, 2H), 0.70-0.58 (m, 2H). Enantiomer 2: LCMS (Method D):RT=5.81 min, m/z: 406.1 [M+H]. ¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s,1H), 7.17 (d, J=8.4 Hz, 1H), 6.91 (d, J=12.9 Hz, 1H), 4.07-3.92 (m, 2H),3.24 (s, 3H), 2.20 (s, 1H), 2.02 (m, 3H), 1.89-1.59 (m, 4H), 1.56-1.38(m, 1H), 1.30-1.14 (m, 1H), 0.94-0.84 (m, 2H), 0.70-0.59 (m, 2H).

Example 421 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((3,3-difluorocyclohexyl)-methoxy)-2-fluorobenzamide

The compound was prepared in a similar manner to Example 420 from5-cyclopropyl-4-((3,3-difluorocyclohexyl)methoxy)-2-fluorobenzoic acid.Two enantiomers were separated with chiral chromatography. Enantiomer 1:LCMS (Method D): RT=6.19 min, m/z: 447.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 11.57 (s, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.95 (d, J=12.8 Hz,1H), 4.10-3.94 (m, 6H), 2.29-1.95 (m, 6H), 1.92-1.58 (m, 4H), 1.57-1.40(m, 1H), 1.30-1.14 (m, 1H), 0.96-0.84 (m, 2H), 0.73-0.60 (m, 2H).Enantiomer 2: LCMS (Method D): RT=6.23 min, m/z: 447.2 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 11.57 (s, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.95 (d,J=12.8 Hz, 1H), 4.10-3.94 (m, 6H), 2.29-1.95 (m, 6H), 1.92-1.58 (m, 4H),1.57-1.40 (m, 1H), 1.30-1.14 (m, 1H), 0.96-0.84 (m, 2H), 0.73-0.60 (m,2H).

Example 422 Synthesis of5-cyclopropyl-4-((3,3-difluorocyclohexyl)methoxy)-2-fluoro-N-(N-methylsulfamoyl)benzamide

The compound was prepared in a similar manner to Example 420 from5-cyclopropyl-4-((3,3-difluorocyclohexyl)methoxy)-2-fluorobenzoic acid.Two enantiomers were separated with chiral chromatography. Enantiomer 1:LCMS (Method D): RT=5.79 min, m/z: 421.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 11.46 (s, 1H), 7.44 (s, 1H), 7.12 (d, J=8.2 Hz, 1H), 6.92 (d,J=12.8 Hz, 1H), 4.07-3.91 (m, 2H), 2.53 (d, J=4.9 Hz, 2H), 2.20 (s, 1H),2.14-1.96 (m, 3H), 1.89-1.40 (m, 5H), 1.35-1.09 (m, 2H), 0.95-0.86 (m,2H), 0.70-0.61 (m, 2H). ¹H NMR (400 MHz, DMSO-d₆) δ 11.46 (s, 1H), 7.44(s, 1H), 7.12 (d, J=8.2 Hz, 1H), 6.92 (d, J=12.8 Hz, 1H), 4.07-3.91 (m,2H), 2.53 (d, J=4.9 Hz, 2H), 2.20 (s, 1H), 2.14-1.96 (m, 3H), 1.89-1.40(m, 5H), 1.35-1.09 (m, 2H), 0.95-0.86 (m, 2H), 0.70-0.61 (m, 2H).Enantiomer 2: LCMS (Method D): RT=5.78 min, m/z: 421.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 11.46 (s, 1H), 7.45 (s, 1H), 7.12 (d, J=8.2 Hz,1H), 6.93 (d, J=12.8 Hz, 1H), 4.08-3.92 (m, 2H), 2.54 (d, J=4.8 Hz, 2H),2.20 (s, 1H), 2.02 (tt, J=8.6, 5.3 Hz, 3H), 1.90-1.58 (m, 4H), 1.58-1.37(m, 1H), 1.31-1.12 (m, 1H), 0.96-0.83 (m, 2H), 0.73-0.61 (m, 2H).

Example 423 Synthesis of5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((3,3-difluorocyclohexyl)-methoxy)-2-fluorobenzamide

The compound was prepared in a similar manner to Example 420 from5-cyclopropyl-4-((3,3-difluorocyclohexyl)methoxy)-2-fluorobenzoic acid.Two enantiomers were separated with chiral chromatography. Enantiomer 1:LCMS (Method D): RT=6.13 min, m/z: 432.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 11.66 (s, 1H), 7.22-7.10 (m, 1H), 6.93 (d, J=13.0 Hz, 1H),4.01 (t, J=6.3 Hz, 2H), 3.11-2.97 (m, 1H), 2.28-1.92 (m, 4H), 1.91-1.59(m, 4H), 1.49 (d, J=13.1 Hz, 1H), 1.34-1.00 (m, 5H), 0.97-0.81 (m, 2H),0.66 (td, J=5.0, 2.4 Hz, 2H). Enantiomer 2: LCMS (Method D): RT=6.14min, m/z: 432.2 [M+H]. ¹H NMR (400 MHz, DMSO-d₆) δ 11.78 (s, 1H), 7.15(d, J=8.3 Hz, 1H), 6.94 (d, J=12.9 Hz, 1H), 4.09-3.93 (m, 2H), 3.11-2.99(m, 1H), 2.29-1.95 (m, 4H), 1.90-1.59 (m, 4H), 1.49 (dd, J=14.5, 11.2Hz, 1H), 1.30-0.99 (m, 5H), 0.95-0.83 (m, 2H), 0.71-0.60 (m, 2H).

Example 424 Synthesis ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzamide

Step 1. Preparation of methyl5-chloro-2-fluoro-4-((4-methylenecyclohexyl)oxy)benzoate

To a suspension of methyltriphenylphosphonium bromide (1.61 g, 4.51mmol) in anhydrous tetrahydrofuran (20 mL) was added a solution ofpotassium tert-butoxide (0.541 g, 4.82 mmol) in anhydroustetrahydrofuran (15 mL) dropwise over 3 minutes at 0° C. The mixture wasstirred under a nitrogen atmosphere at 0° C. for 1 h. To this solutionwas added a solution of methyl5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoate (1.05 g, 3.48 mmol)in anhydrous tetrahydrofuran (15 mL) dropwise over 3 minutes. Themixture was stirred at ambient temperature for 21 h, then diluted withwater (200 mL). The mixture was extracted with ethyl acetate (200 mL)and the organic phase was washed with water (50 mL) and brine (150 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo. The residue was purified by column chromatography with a gradientof 0-10% ethyl acetate in hexanes to afford the title compound as acolorless syrup (0.866 g, 83% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.94 (d,J=7.7 Hz, 1H), 6.67 (d, J=12.2 Hz, 1H), 4.68 (s, 2H), 4.56-4.50 (m, 1H),3.87 (s, 3H), 2.48-2.40 (m, 2H), 2.17-2.09 (m, 2H), 1.92-1.86 (m, 4H);MS (ES+) m/z 299.00 (M+1).

Step 2. Preparation of methyl5-chloro-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzoate

Following the procedure as described in Example 342 Step 2 and makingnon-critical variations to replace cyclohexenylmethanol with methyl5-chloro-2-fluoro-4-((4-methylenecyclohexyl)oxy)benzoate, the titlecompound was obtained as a colorless syrup (0.769 g, 85% yield): ¹H NMR(300 MHz, CDCl₃) δ 7.95 (d, J=7.7 Hz, 1H), 6.68 (d, J=12.4 Hz, 1H),4.49-4.41 (m, 1H), 3.88 (s, 3H), 1.99-1.78 (m, 4H), 1.53-1.32 (m, 4H),0.33-0.27 (m, 4H).

Step 3. Preparation of methyl5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzoate

Following the procedure as described in Example 374 Step 3 and makingnon-critical variations to replace tert-butyl5-chloro-4-((1-cyanocyclohexyl)methoxy)-2-fluorobenzoate with methyl5-chloro-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzoate, the titlecompound was obtained as a colorless syrup (0.389 g, 72% yield): ¹H NMR(300 MHz, CDCl₃) δ 7.42 (d, J=8.5 Hz, 1H), 6.56 (d, J=13.0 Hz, 1H),4.46-4.39 (m, 1H), 3.86 (s, 3H), 2.10-2.01 (m, 1H), 1.99-1.90 (m, 2H),1.86-1.76 (m, 2H), 1.54-1.24 (m, 4H), 0.96-0.84 (m, 3H), 0.66-0.60 (m,2H), 0.32-0.26 (m, 4H); MS (ES+) m/z 287.05 (M−31).

Step 4. Preparation of5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzoic acid

Following the procedure as described in Example 357 Step 6 and makingnon-critical variations to replace methyl5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoate with methyl5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzoate, the titlecompound was obtained as a colorless syrup that was carried forwardwithout further purification (0.393 g, quant. yield).

Step 5. Preparation ofN-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzamide

Following the procedure as described in Example 357 Step 4 and makingnon-critical variations to replace5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoic acid with5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzoic acid andmethanol with azetidine-1-sulfonamide, the title compound was obtainedas a colorless solid (0.029 g, 12% yield): ¹H NMR (300 MHz, DMSO-d₆)δ11.57 (br s, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.01 (d, J=13.2 Hz, 1H),4.67-4.61 (m, 1H), 4.00 (t, J=7.7 Hz, 4H), 2.17-1.98 (m, 3H), 1.90-1.83(m, 2H), 1.72-1.61 (m, 2H), 1.49-1.29 (m, 4H), 0.90-0.84 (m, 2H),0.68-0.63 (m, 2H), 0.30-0.19 (m, 4H); MS (ES−) m/z 421.15 (M−1).

Example 425 Synthesis of5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(spiro[2.5]octan-6-yloxy)benzamide

Following the procedure as described in Example 357 Step 4 and makingnon-critical variations to replace5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoic acid with5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzoic acid andmethanol with methanesulfonamide, the title compound was obtained as acolorless solid (0.121 g, 53% yield): ¹H NMR (300 MHz, CDCl₃) δ8.69 (d,J=16.2 Hz, 1H), 7.55 (d, J=9.2 Hz, 1H), 6.58 (d, J=14.8 Hz, 1H),4.49-4.42 (m, 1H), 3.39 (s, 3H), 2.11-1.77 (m, 5H), 1.54-1.21 (m, 4H),0.96-0.89 (m, 2H), 0.67-0.61 (m, 2H), 0.34-0.27 (m, 4H); MS (ES−) m/z380.20 (M−1).

Example 426

Using procedures and intermediates similar to those described herein,additional representative compounds of formula (I) were prepared.Biological data for these compounds is provided in Table 2 below.

Example 427 Electrophysiological Assay (In Vitro Assay)

Patch voltage clamp electrophysiology allows for the direct measurementand quantification of block of voltage-gated sodium channels (NaV's),and allows the determination of the time- and voltage-dependence ofblock which has been interpreted as differential binding to the resting,open, and inactivated states of the sodium channel (Hille, B., Journalof General Physiology (1977), 69: 497-515).

The following patch voltage clamp electrophysiology studies wereperformed on representative compounds of the invention using humanembryonic kidney cells (HEK), permanently transfected with an expressionvector containing the full-length cDNA coding for the desired humansodium channel α-subunit, grown in culture media containing 10% FBS, 1%PSG, and 0.5 mg/mL G418 at 37° C. with 5% CO2. HEK cells used for theelectrophysiology (EP) recordings had a passage number of less than 40for all studies and were used within three days from the time ofplating. NaV1.7 and NaV1.5 cDNAs (NM_(—)002977 and AC137587; SCN5A,respectively) were stably expressed in HEK-293 cells. The β1 subunit wascoexpressed in both the NaV1.7 and NaV1.5 cell lines.

Sodium currents were measured using the patch clamp technique in thewhole-cell configuration using either a PatchXpress automated voltageclamp or manually using an Axopatch 200B (Axon Instruments) or Model2400 (A-M systems) amplifier. The manual voltage clamp protocol was asfollows: Borosilicate glass micropipettes were fire-polished to a tipdiameter yielding a resistance of 2-4 Mohms in the working solutions.The pipette was filled with a solution comprised of: 5 mM NaCl, 10 mMCsCl, 120 mM CsF, 0.1 mM CaCl2, 2 mM MgCl2, 10 mM HEPES, 10 mM EGTA; andadjusted to pH 7.2 with CsOH. The external solution had the followingcomposition: 140 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES;and adjusted to pH 7.4 with NaOH. In some studies, the external sodiumwas reduced by equimolar replacement with choline. Osmolarity in the CsFinternal and NaCl external solutions was adjusted to 300 mOsm/kg and 310mOsm/kg with glucose, respectively. All recordings were performed atambient temperature in a bath chamber with a volume of 150 μL. Controlsodium currents were measured in 0.5% DMSO. Controls and representativecompounds of the invention were applied to the recording chamber througha 4-pinch or 8-pinch valve bath perfusion system manufactured by ALAScientific Instruments.

Currents were recorded at 40 kHz sampling frequency, filtered at 5 Hz,and stored using a Digidata-1322A analogue/digital interface with thepClamp software (Axon Instruments). Series resistance compensation wasapplied (60-80%). Cells were rejected if currents showed inadequatevoltage control (as judged by the IV relationship during stepwiseactivation). All statistics in this study are given as mean±SD.

The membrane potential was maintained at a voltage where inactivation ofthe channel is complete (which was −60 mV for both NaV1.7 and NaV1.5).The voltage is then stepped back to a very negative (Vhold=150 mV)voltage for 20 ms and then a test pulse is applied to quantify thecompound block. The 20 ms brief repolarization was long enough forcompound-free channels to completely recover from fast inactivation, butthe compound-bound channels recovered more slowly such that negligiblerecovery could occur during this interval. The percent decrease insodium current following wash-on of compound was taken as the percentblock of sodium channels.

Compounds of the invention, when tested in this model, demonstratedaffinities for the inactivated state of NaV1.7 and NaV1.5 as set forthbelow in Table 2.

TABLE 2 NaV1.7 395 EP_PX 293 EP_PX 293 Memb Binding hNav1.5 hNav1.7(IC50) (IC50) (IC50) (micromolar) (micromolar) (micromolar) 1 9.99 26.86 3 10.0 4 10.0 5 0.15 0.0201 6 0.029 1.9 0.0055 7 10.0 8 0.012 1.070.0038 9 0.040 0.0052 10 0.26 0.0082 11 0.029 0.0087 12 0.074 0.0069 130.41 0.123 14 0.32 0.0377 15 0.77 0.171 16 0.12 0.0312 17 10.0 18 1.20.356 19 0.092 0.0386 20 0.09 0.0563 21 1.06 0.107 22 0.19 0.0134 230.013 0.0229 24 10.0 25 0.22 0.027 26 0.12 0.772 0.0281 27 10.0 10.0 2810.0 2.25 29 10.0 30 0.14 0.0099 31 1.4 0.146 32 0.14 33 0.19 0.0937 340.038 0.0658 35 10.0 36 0.12 0.0077 37 10.0 38 0.603 39 0.009 40 0.14 or0.04 0.013 or 0.0423 41 0.14 or 0.04 0.013 or 0.0423 42 0.044 43 0.0722.58 0.0179 44 0.005 45 0.005 46 0.005 0.0033 47 0.007 0.0606 0.0107 480.007 0.0046 49 0.003 0.101 0.0022 50 0.029 51 0.009 52 0.006 53 0.10 540.058 55 0.009 0.0031 56 0.48 57 0.077 0.653 0.0154 58 0.026 59 0.065 600.001 0.159 0.00030 61 0.051 1.95 0.0076 62 0.058 63 0.0021 0.0030 640.002 0.0515 0.00040 65 0.17 66 0.18 67 0.13 68 0.73 69 0.097 0.0343 700.021 0.0368 71 0.37 72 0.076 0.0154 73 0.19 74 0.055 75 0.77 76 0.19 770.086 78 0.033 79 0.16 0.0854 80 1.68 81 0.122 82 0.294 0.0416 83 0.10684 0.0162 85 0.016 86 0.003 0.70 0.00131 87 0.081 88 0.121 89 0.234 900.094 91 1.21 92 0.221 3.76 0.0531 93 0.086 94 0.224 95 0.017 96 0.16497 0.051 0.0073 98 0.382 99 0.558 100 0.299 101 0.322 102 0.672 1030.603 104 0.053 105 0.264 106 0.158 0.0847 107 0.044 108 0.803 109 0.017110 0.086 111 0.181 112 0.117 113 0.080 114 0.044 115 0.009 116 0.167117 7.12 118 1.32 119 0.491 120 0.205 121 0.057 122 0.093 123 0.166 1240.738 125 0.23 126 0.392 127 0.339 128 0.291 0.0303 129 0.283 130 0.542131 0.138 132 0.419 133 0.125 134 0.067 135 0.535 7.82 0.0304 136 0.21137 0.295 138 1.12 139 0.281 140 0.885 141 0.273 142 3.52 143 0.30 1440.166 145 0.009 0.743 0.0036 146 0.00432 0.427 0.0153 147 0.010 0.110.0067 148 0.001 0.026 0.0014 149 0.353 150 0.001 0.422 0.0043 151 0.021152 0.027 0.0106 153 0.001 0.714 154 0.004 155 0.005 0.014 156 0.003 1570.012 158 0.002 159 0.010 0.326 160 1.64 161 0.014 162 0.010 163 0.001164 0.003 165 0.152 166 0.027 5.23 0.0040 167 0.012 168 0.023 0.0220.0092 169 0.003 0.144 0.0249 170 0.004 0.006 171 0.002 0.002 172 0.12173 0.29 174 1.1 175 0.006 0.67 0.001 176 0.05 177 0.07 178 0.25 179 1.7180 1.2 181 0.004 182 0.89 183 21.5 184 0.012 185 0.006 0.04 0.001 1860.018 0.14 0.004 187 0.99 188 0.88 189 0.31 190 0.0031 191 0.001 0.130.009 192 0.005 193 0.066 194 1.2 195 0.008 196 0.012 197 0.022 1980.014 3.5 0.02 199 0.015 200 0.005 201 0.007 202 0.04 203 0.54 204 0.012205 0.022 206 0.16 207 0.012 208 0.007 209 0.016 210 0.008 211 0.002 2122.3 213 1.1 214 0.9 215 0.99 216 0.043 217 0.006 0.63 0.008 218 0.01 2190.007 0.95 0.005 220 0.005 221 0.003 0.35 0.003 222 0.009 223 0.18 2240.009 0.005 225 0.1 226 0.03 227 0.06 228 0.046 229 0.63 230 0.03 2310.036 232 0.08 233 0.005 0.43 0.02 234 0.03 235 0.003 236 0.035 2370.067 238 0.02 239 0.004 0.008 240 0.004 0.008 241 0.13 242 0.02 243 0.1244 0.077 245 0.004 0.01 246 0.01 0.004 247 0.018 248 0.005 249 0.0040.09 0.002 250 0.010 251 0.004 0.006 252 253 0.036 254 255 0.047 2560.038 257 0.09 258 0.011 259 0.02 260 0.61 261 0.04 262 0.003 0.13 0.008263 264 265 0.13 266 0.049 267 0.06 268 0.21 269 0.006 0.16 0.002 2700.002 0.002 271 272 273 274 275 276 277 278 279 280 0.29 7.5 0.063 2810.72 15.3 0.37 282 0.009 0.02 283 0.009 21.6 0.03 284 0.019 0.01 2850.026 0.023 286 0.004 0.006 287 1.5 1 288 0.007 0.013 289 0.14 0.062 2900.016 0.02 291 0.043 0.035 292 0.12 0.088 293 0.18 0.14 294 0.005 0.046295 0.01 0.021 296 0.16 0.31 297 0.011 0.10 298 0.014 0.041 299 0.0310.08 300 0.045 0.23 301 0.014 0.36 302 0.23 0.08 303 0.07 0.032 3040.074 0.024 305 0.31 1.4 306 1.3 4.6 307 1.3 5.2 308 0.02 0.18 309 0.0060.079 310 0.084 0.01 311 0.03 0.053 312 0.004 0.003 313 0.007 0.012 3140.025 0.077 315 0.019 0.019 316 0.26 0.3 317 0.08 0.18 318 0.004 0.062319 0.029 0.30 320 0.017 0.14 321 0.2 0.26 322 0.081 0.20 323 0.37 2.3324 0.46 4.3 325 0.27 2.5 326 0.19 1.5 327 0.003 0.012 328 0.024 0.07329 0.004 0.02 330 0.025 0.091 331 0.45 0.71 332 0.004 0.027 333 0.020.1 334 0.011 0.043 335 0.010 0.056 336 0.11 0.27 337 0.043 0.14 3380.98 4.4 339 0.31 3.3 340 0.27 0.28 341 342 0.021 0.018 343 0.023 0.029344 0.021 0.019 345 0.008 0.009 346 0.015 0.034 347 0.014 0.067 3480.009 0.026 349 0.004 0.065 350 0.73 0.61 351 0.004 0.024 352 0.044 0.12353 0.13 0.24 354 0.024 0.17 355 0.022 0.11 356 0.074 0.52 357 0.0160.12 358 0.012 0.062 359 0.007 0.12 360 0.004 0.061 361 0.006 0.053 3620.0063 0.22 363 0.023 0.067 364 0.004 0.30 365 0.021 0.024 366 0.010.094 367 0.13 1.3 368 0.36 0.7 369 0.192 0.075 370 0.05 0.09 371 0.220.48 372 0.007 0.011 373 0.004 0.002 374 0.39 0.3 375 0.009 0.007 3760.02 0.03 377 0.008 0.084 378 0.005 0.34 379 0.004 0.14 380 0.004 0.08381 0.036 0.021 382 0.022 0.035 383 0.012 0.35 384 0.005 0.082 385 0.0340.6 386 387 0.02 1.2 388 0.007 0.28 389 0.003 0.004 390 0.003 0.019 3910.009 0.002 392 0.005 0.003 393 0.028 0.89 394 0.011 0.52 395 0.06 0.39396 0.025 0.074 397 0.032 0.20 398 0.006 1.3 399 0.006 0. 400 0.0200.097 401 0.022 0.043 402 0.022 0.30 403 0.09 0.91 404 0.023 0.057 4050.066 0.93 406 0.027 0.42 407 408 409 410 411 412 0.003 0.023 413 0.0040.003 414 0.008 0.028 415 0.006 0.01 416 0.005 0.009 417 0.10 0.19 4180.005 0.012 419 0.004 0.058 420 0.006 0.087 421 0.004 0.032 422 0.0040.033 423 1.4 3.6 424 0.011 0.047 425 0.004 0.059 426 0.002 0.051 4270.003 0.13 428 0.004 0.012 429 0.008 0.10

NaV1.7 395 EP_PX 293 EP_PX 293 Memb Binding hNav1.5 hNav1.7 (IC50)(IC50) (IC50) (micromolar) (micromolar) (micromolar) 430 0.003 0.01 4310.013 0.01 432 0.022 0.032 433 0.004 434 0.011 435 0.003 436 0.009 437438 439 0.028 440 0.011 2.54 0.014 441 0.01 442 0.006 or 0.004 443 0.006or 0.004 444 0.010 0.326 445 0.0093 0.743 0.0036 446 0.0016 0.16 0.0031447 0.0042 448 0.018 0.94 0.0078 449 0.004 450 1.2 451 0.27 452 7.1 4530.95 454 0.018 455

Example 428 Analgesia Induced by Sodium Channel Blockers

Heat Induced Tail Flick Latency Test

In this test, the analgesia effect produced by administering a compoundof the invention can be observed through heat-induced tail-flick inmice. The test includes a heat source consisting of a projector lampwith a light beam focused and directed to a point on the tail of a mousebeing tested. The tail-flick latencies, which are assessed prior to drugtreatment, and in response to a noxious heat stimulus, i.e., theresponse time from applying radiant heat on the dorsal surface of thetail to the occurrence of tail flick, are measured and recorded at 40,80, 120, and 160 minutes.

For the first part of this study, 65 animals undergo assessment ofbaseline tail flick latency once a day over two consecutive days. Theseanimals are then randomly assigned to one of the 11 different treatmentgroups including a vehicle control, a morphine control, and 9 compoundsat 30 mg/Kg are administered intramuscularly. Following doseadministration, the animals are closely monitored for signs of toxicityincluding tremor or seizure, hyperactivity, shallow, rapid or depressedbreathing and failure to groom. The optimal incubation time for eachcompound is determined via regression analysis. The analgesic activityof the test compounds is expressed as a percentage of the maximumpossible effect (% MPE) and is calculated using the following formula:

$\% \mspace{14mu} {MPE}\mspace{14mu} \frac{{{Postdrug}\mspace{14mu} {latency}} - {{Predrug}\mspace{14mu} {latency}}}{{{Cut}\text{-}{off}\mspace{14mu} {time}\mspace{14mu} \left( {10{\mspace{14mu} \;}s} \right)} - {{Predrug}\mspace{14mu} {latency}}} \times 100\%$

where:

Postdrug latency=the latency time for each individual animal takenbefore the tail is removed (flicked) from the heat source afterreceiving drug.

Predrug latency=the latency time for each individual animal taken beforethe tail is flicked from the heat source prior to receiving drug.

Cut-off time (10 s)=is the maximum exposure to the heat source.

Acute Pain (Formalin Test)

The formalin test is used as an animal model of acute pain. In theformalin test, animals are briefly habituated to the plexiglass testchamber on the day prior to experimental day for 20 minutes. On the testday, animals are randomly injected with the test articles. At 30 minutesafter drug administration, 50 L of 10% formalin is injectedsubcutaneously into the plantar surface of the left hind paw of therats. Video data acquisition begins immediately after formalinadministration, for duration of 90 minutes.

The images are captured using the Actimetrix Limelight software whichstores files under the *.llii extension, and then converts it into theMPEG-4 coding. The videos are then analyzed using behaviour analysissoftware “The Observer 5.1”, (Version 5.0, Noldus InformationTechnology, Wageningen, The Netherlands). The video analysis isconducted by watching the animal behaviour and scoring each according totype, and defining the length of the behaviour (Dubuisson and Dennis,1977). Scored behaviours include: (1) normal behaviour, (2) putting noweight on the paw, (3) raising the paw, (4) licking/biting or scratchingthe paw. Elevation, favoring, or excessive licking, biting andscratching of the injected paw indicate a pain response. Analgesicresponse or protection from compounds is indicated if both paws areresting on the floor with no obvious favoring, excessive licking, bitingor scratching of the injected paw.

Analysis of the formalin test data is done according to two factors: (1)Percent Maximal Potential Inhibitory Effect (% MPIE) and (2) pain score.The % MPIEs is calculated by a series of steps, where the first is tosum the length of non-normal behaviours (behaviours 1, 2, 3) of eachanimal. A single value for the vehicle group is obtained by averagingall scores within the vehicle treatment group. The following calculationyields the MPIE value for each animal:

MPIE (%)=100−[(treatment sum/average vehicle value)×100%]

The pain score is calculated from a weighted scale as described above.The duration of the behaviour is multiplied by the weight (rating of theseverity of the response), and divided by the total length ofobservation to determine a pain rating for each animal. The calculationis represented by the following formula:

Pain rating=[0(To)+1(T1)+2(T2)+3(T3)]/(To+T1+T2+T3)

CFA Induced Chronic Inflammatory Pain

In this test, tactile allodynia is assessed with calibrated von Freyfilaments. Following a full week of acclimatization to the vivariumfacility, 150 L of the “Complete Freund's Adjuvant” (CFA) emulsion (CFAsuspended in an oil/saline (1:1) emulsion at a concentration of 0.5mg/mL) is injected subcutaneously into the plantar surface of the lefthind paw of rats under light isoflurane anaesthesia. Animals are allowedto recover from the anaesthesia and the baseline thermal and mechanicalnociceptive thresholds of all animals are assessed one week after theadministration of CFA. All animals are habituated to the experimentalequipment for 20 minutes on the day prior to the start of theexperiment. The test and control articles are administrated to theanimals, and the nociceptive thresholds measured at defined time pointsafter drug administration to determine the analgesic responses to eachof the six available treatments. The time points used are previouslydetermined to show the highest analgesic effect for each test compound.

Thermal nociceptive thresholds of the animals are assessed using theHargreaves test. Animals are placed in a Plexiglas enclosure set on topof an elevated glass platform with heating units. The glass platform isthermostatically controlled at a temperature of approximately 30° C. forall test trials. Animals are allowed to accommodate for 20 minutesfollowing placement into the enclosure until all exploration behaviourceases. The Model 226 Plantar/Tail Stimulator Analgesia Meter (IITC,Woodland Hills, Calif.) is used to apply a radiant heat beam fromunderneath the glass platform to the plantar surface of the hind paws.During all test trials, the idle intensity and active intensity of theheat source are set at 1 and 45 respectively, and a cut off time of 20seconds is employed to prevent tissue damage.

The response thresholds of animals to tactile stimuli are measured usingthe Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.) following the Hargreaves test. Animals areplaced in an elevated Plexiglas enclosure set on a mire mesh surface.After 10 minutes of accommodation, pre-calibrated Von Frey hairs areapplied perpendicularly to the plantar surface of both paws of theanimals in an ascending order starting from the 0.1 g hair, withsufficient force to cause slight buckling of the hair against the paw.Testing continues until the hair with the lowest force to induce a rapidflicking of the paw is determined or when the cut off force ofapproximately 20 g is reached. This cut off force is used because itrepresent approximately 10% of the animals' body weight and it serves toprevent raising of the entire limb due to the use of stiffer hairs,which would change the nature of the stimulus.

Postoperative Models of Nociception

In this model, the hypealgesia caused by an intra-planar incision in thepaw is measured by applying increased tactile stimuli to the paw untilthe animal withdraws its paw from the applied stimuli. While animals areanaesthetized under 3.5% isofluorane, which is delivered via a nosecone, a 1 cm longitudinal incision is made using a number 10 scalpelblade in the plantar aspect of the left hind paw through the skin andfascia, starting 0.5 cm from the proximal edge of the heel and extendingtowards the toes. Following the incision, the skin is apposed using 2,3-0 sterilized silk sutures. The injured site is covered with Polysporinand Betadine. Animals are returned to their home cage for overnightrecovery.

The withdrawal thresholds of animals to tactile stimuli for bothoperated (ipsilateral) and unoperated (contralateral) paws can bemeasured using the Model 2290 Electrovonfrey anesthesiometer (IITC LifeScience, Woodland Hills, Calif.). Animals are placed in an elevatedPlexiglas enclosure set on a mire mesh surface. After at least 10minutes of acclimatization, pre-calibrated Von Frey hairs are appliedperpendicularly to the plantar surface of both paws of the animals in anascending order starting from the 10 g hair, with sufficient force tocause slight buckling of the hair against the paw. Testing continuesuntil the hair with the lowest force to induce a rapid flicking of thepaw is determined or when the cut off force of approximately 20 g isreached. This cut off force is used because it represent approximately10% of the animals' body weight and it serves to prevent raising of theentire limb due to the use of stiffer hairs, which would change thenature of the stimulus.

Neuropathic Pain Model; Chronic Constriction Injury

Briefly, an approximately 3 cm incision is made through the skin and thefascia at the mid thigh level of the animals' left hind leg using a no.10 scalpel blade. The left sciatic nerve is exposed via blunt dissectionthrough the biceps femoris with care to minimize haemorrhagia. Fourloose ligatures are tied along the sciatic nerve using 4-0non-degradable sterilized silk sutures at intervals of 1 to 2 mm apart.The tension of the loose ligatures is tight enough to induce slightconstriction of the sciatic nerve when viewed under a dissectionmicroscope at a magnification of 4 fold. In the sham-operated animal,the left sciatic nerve is exposed without further manipulation.Antibacterial ointment is applied directly into the wound, and themuscle is closed using sterilized sutures. Betadine is applied onto themuscle and its surroundings, followed by skin closure with surgicalclips.

The response thresholds of animals to tactile stimuli are measured usingthe Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.). Animals are placed in an elevated Plexiglasenclosure set on a mire mesh surface. After 10 minutes of accommodation,pre-calibrated Von Frey hairs are applied perpendicularly to the plantarsurface of both paws of the animals in an ascending order starting fromthe 0.1 g hair, with sufficient force to cause slight buckling of thehair against the paw. Testing continues until the hair with the lowestforce to induce a rapid flicking of the paw is determined or when thecut off force of approximately 20 g is reached. This cut off force isused because it represents approximately 10% of the animals' body weightand it serves to prevent raising of the entire limb due to the use ofstiffer hairs, which would change the nature of the stimulus.

Thermal nociceptive thresholds of the animals are assessed using theHargreaves test. Following the measurement of tactile thresholds,animals are placed in a Plexiglass enclosure set on top of an elevatedglass platform with heating units. The glass platform isthermostatically controlled at a temperature of approximately 24 to 26°C. for all test trials. Animals are allowed to accommodate for 10minutes following placement into the enclosure until all explorationbehaviour ceases. The Model 226 Plantar/Tail Stimulator Analgesia Meter(IITC, Woodland Hills, Calif.) is used to apply a radiant heat beam fromunderneath the glass platform to the plantar surface of the hind paws.During all test trials, the idle intensity and active intensity of theheat source are set at 1 and 55 respectively, and a cut off time of 20seconds is used to prevent tissue damage.

Neuropathic Pain Model: Spinal Nerve Ligation

The spinal nerve ligation (SNL) neuropathic pain model is used as ananimal (i.e. rat) model of neuropathic pain. In the SNL test, the lumbarroots of spinal nerves L5 and L6 are tightly ligated to cause nerveinjury, which results in the development of mechanical hyperalgesia,mechanical allodynia and thermal hypersensitivity. The surgery isperformed two weeks before the test day in order for the pain state tofully develop in the animals. Several spinal nerve ligation variationsare used to characterize the analgesic properties of a compound of theinvention.

(1) Ligation of the L5 spinal nerve;(2) Ligation of the L5 and L6 spinal nerves;(3) Ligation and transection of the L5 spinal nerve;(4) Ligation and transection of the L5 and L6 spinal nerves; or(5) Mild irritation of the L4 spinal nerve in combination with any oneof the above (1)-(4).

While the animals are anaesthetized under 3.5% isofluorane delivered viaa nose cone, an approximately 2.5 cm longitudinal incision is made usinga number 10 scalpel blade in the skin just lateral to the dorsalmidline, using the level of the posterior iliac crests as the midpointof the incision. Following the incision, the isoflourane is readjustedto maintenance levels (1.5%-2.5%). At mid-sacral region, an incision ismade with the scalpel blade, sliding the blade along the side of thevertebral column (in the saggital plane) until the blade hits thesacrum. Scissors tips are introduced through the incision and the muscleand ligaments are removed from the spine to expose 2-3 cm of thevertebral column. The muscle and fascia are cleared from the spinalvertebra in order to locate the point where the nerve exits from thevertebra. A small glass hook is placed medial to the spinal nerves andthe spinal nerves are gently elevated from the surrounding tissues. Oncethe spinal nerves have been isolated, a small length of non-degradable6-0 sterilized silk thread is wound twice around the ball at the tip ofthe glass hook and passed back under the nerve. The spinal nerves arethen firmly ligated by tying a knot, ensuring that the nerve bulges onboth sides of the ligature. The procedure may be repeated as needed. Insome animals, the L4 spinal nerve may be lightly rubbed (up to 20 times)with the small glass hook to maximize the development of neuropathicpain. Antibacterial ointment is applied directly into the incision, andthe muscle is closed using sterilized sutures. Betadine is applied ontothe muscle and its surroundings, followed by skin closure with surgicalstaples or sterile non-absorable monofilament 5-0 nylon sutures.

The analgesic effect produced by topical administration of a compound ofthe invention to the animals can then be observed by measuring the pawwithdrawal threshold of animals to mechanical tactile stimuli. These maybe measured using either the mechanical allodynia procedure or themechanical hyperalgesia procedure as described below. Afterestablishment of the appropriate baseline measurements by either method,topical formulation of a compound of the invention is applied on theipsilateral ankle and foot. The animals are then placed in plastictunnels for 15 minutes to prevent them from licking the treated area andremoving the compound. Animals are placed in the acrylic enclosure for15 minutes before testing the ipsilateral paw by either of the methodsdescribed below, and the responses are recorded at 0.5, 1.0 and 2.0 hourpost treatment.

A. Mechanical Allodynia Method

The pain threshold of animals to mechanical alloydnia for both operatedand control animals can be measured approximately 14 days post-surgeryusing manual calibrated von Frey filaments as follows. Animals areplaced in an elevated plexiglass enclosure set on a mire mesh surface.Animals are allowed to acclimate for 20-30 minutes. Pre-calibrated VonFrey hairs are applied perpendicularly to the plantar surface of theipsilateral paw of the animals starting from the 2.0 g hair, withsufficient force to cause slight buckling of the hair against the paw toestablish the baseline measurements. Stimuli are presented in aconsecutive manner, either in an ascending or descending order until thefirst change in response is noted, after which four additional reponsesare recorded for a total of six responses. The six responses measured ingrams are entered into a formula as described by Chaplan, S. R. et al.,J. Neurosci. Methods, 1994 July; 53(1):55-63, and a 50% withdrawalthreshold is calculated. This constitutes the mechanical allodyniavalue.

B. Mechanical Hyperalgesia Method

The response thresholds of animals to tactile stimuli were measuredusing the Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.). Animals were placed in an elevated Plexiglasenclosure set on a wire mesh surface. After 15 minutes of accommodationin this enclosure, a von Frey hair was applied perpendicularly to theplantar surface of the ipsilateral hind paws of the animals, withsufficient force, measured in grams, to elicit a crisp response of thepaw. The response indicated a withdrawal from the painful stimulus andconstituted the efficacy endpoint. The data were expressed as percentchange from baseline threshold measured in grams.

Example 427

In Vivo Assay for Treatment of Pruritis

The compounds of the invention can be evaluated for their activity asantipruritic agents by in vivo test using rodent models. One establishedmodel for peripherally elicited pruritus is through the injection ofserotonin into the rostral back area (neck) in hairless rats. Prior toserotonin injections (e.g., 2 mg/mL, 50 μL), a dose of a compound of thepresent invention can be applied systemically through oral, intravenousor intraperitoneal routes or topically to a circular area fixed diameter(e.g. 18 mm). Following dosing, the serotonin injections are given inthe area of the topical dosing. After serotonin injection the animalbehaviour is monitored by video recording for 20 min-1.5 h, and thenumber of scratches in this time compared to vehicle treated animals.Thus, application of a compound of the current invention could suppressserotonin-induced scratching in rats.

Example 428 Tritiated Aryl Sulfonamide Binding to Membranes Isolatedfrom Cells that Heterologously Express hNav1.7 and the β1 Subunit

Preparation of membranes containing recombinantly expressed sodiumchannels: Frozen recombinant cell pellets were thawed on ice and dilutedto 4 times the cell pellet weight with ice cold 50 mM Tris HCl, pH 7.4buffer. The cell suspensions were homogenized on ice using a motorizedglass dounce homogeniser. Homogenates were further diluted 8.4 timeswith ice cold 50 mM Tris HCl, pH 7.4 buffer and then centrifuged at200×g at 4° C. for 15 min. The supernatants were collected andcentrifuged at 10000×g at 4° C. for 50 min. The pellets were thenre-suspended in 100 mM NaCl, 20 mM Tris HCl, pH 7.4 buffer containing 1%v/v protease inhibitors (Calbiochem) and re-homogenized on ice. Thehomogenized membranes were then processed through a syringe equippedwith a 26 gauge needle. Protein concentrations were determined byBradford Assay and the membranes were stored at −80° C.

Radioligand Binding Studies: Saturation experiments. A representativecompound of formula (I) was tritiated. Three tritiums were incorporatedin place of methyl hydrogens to generate [³H]compound. Binding of thisradioligand was preformed in 5 mL borosilicate glass test tubes at roomtemperature. Binding was initiated by adding membranes to increasingconcentrations of [³H]compound in 100 mM NaCl, 20 mM Tris HCl, pH 7.4buffer containing 0.01% w/v bovine serum albumin (BSA) for 18 h.Non-specific binding was determined in the presence of 1 μM unlabelledcompound. After 18 h, the reactants were filtered through GF/C glassfiber filters presoaked in 0.5% w/v polyethylene imine. Filters werewashed with 15 mL ice cold 100 mM NaCl, 20 mM Tris HCl, pH7.4 buffercontaining 0.25% BSA to separate bound from free ligand. [³H]compoundbound to filters was quantified by liquid scintillation counting.

Competitive Binding Experiments.

Binding reactions were preformed in 96-well polypropylene plates at roomtemperature for 18 h. In 360 μL, membranes were incubated with 100 μM[³H]compound and increasing concentrations of Test Compound.Non-specific binding was defined in the presence of 1 μM unlabelledcompound. Reactions were transferred and filtered through 96-well glassfiber/C filter plates presoaked with 0.5% polyethylene imine. Thefiltered reactions were washed 5 times with 200 L ice cold buffercontaining 0.25% BSA. Bound radioactivity was determined by liquidscintillation counting.

Data Analysis: For saturation experiments, non-specific binding wassubtracted from total binding to provide specific binding and thesevalues were recalculated in terms of pmol ligand bound per mg protein.Saturation curves were constructed and dissociation constants werecalculated using the single site ligand binding model:Beq=(Bmax*X)/(X+Kd), where Beq is the amount of ligand bound atequilibrium, Bmax is the maximum receptor density, Kd is thedissociation constant for the ligand, and X is the free ligandconcentration. For competition studies percent inhibition was determinedand IC₅₀ values were calculated using a 4 parameter logistic model (%inhibition=(A+((B−A)/(1+((x/C)̂D)))) using XLfit, where A and B are themaximal and minimum inhibition respectively, C is the IC₅₀ concentrationand D is the (Hill) slope.

Compounds of the invention, when tested in this model, demonstratedaffinities for the inactivated state of NaV1.7 membrane binding (as setforth in Table 2).

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon patent publications referred to in this specification areincorporated herein by reference in their entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

We claim:
 1. A compound selected from a compound of Formula I:

and pharmaceutically acceptable salts thereof, wherein in Formula I: R¹ is C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₁₂ cycloalkyl, C-linked C₂₋₁₁ heterocycloalkyl, heteroaryl, or —NR^(1A)R^(1B), wherein R^(1A) and R^(1B) are each independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, C₁₋₈ alkoxy, (6-10 membered aryl)-(X^(R1))₀₋₁—, (5-10 membered heteroaryl)-(X^(R1))₀₋₁—, and wherein R^(1A) and R^(1B) are optionally combined to form a 3 to 9 membered heterocyclic ring optionally comprising 1 additional heteroatom selected from N, O and S and optionally fused thereto is a benzene or pyridine ring; X^(R1) is selected from the group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene; and wherein the aliphatic and aromatic portions of R¹ are optionally substituted with from 1 to 5 R^(R1) substituents selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂, ═O, —(X^(1R))₀₋₁NR^(R1a)R^(R1b), —(X^(1R))₀₋₁OR^(R1a), —(X^(1R))₀₋₁SR^(R1a), —(X^(1R))₀₋₁N(R^(R1a))C(═O)OR^(R1c), —(X^(1R))₀₋₁OC(═O)N(R^(R1a))(R^(R1b)), —(X^(1R))₀₋₁N(R^(R1a))C(═O)N(R^(R1a))(R^(R1b)), —(X^(1R))₀₋₁C(═O)N(R^(R1a))(R^(R1b)), —(X^(1R))₀₋₁N(R^(R1a))C(═O)R^(R1b), —(X^(1R))₀₋₁C(═O)OR^(R1a), —(X^(1R))₀₋₁OC(═O)R^(R1a), —(X^(1R))₀₋₁—P(═O)(OR^(R1a))(OR^(R1b)), —(X^(1R))₀₋₁S(O)₁₋₂R^(R1c), —(X^(1R))₀₋₁S(O)₁₋₂N(R^(R1a))(R^(R1b)), —(X^(1R))₀₋₃N(R^(R1a))S(O)₁₂N(R^(R1a))(R^(R1b)) and —(X^(1R))₀₋₁N(R^(R1a))S(O)₁₋₂(R^(R1c)), wherein X^(1R) is selected from the group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene; wherein R^(R1a) and R^(R1b) are independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, heteroaryl, and C₂₋₇ heterocycloalkyl; R^(R1c) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, heteroaryl, and C₂₋₇ heterocycloalkyl; R^(N) is hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; B is C or N; R², R³ and R⁴ are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ alkoxy, and R³ is absent when B is nitrogen; R⁵ is selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₈ cycloalkyl, C₂₋₇ heterocycloalkyl, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl or C₂₋₇ heterocycloalkyl is further optionally substituted with from 1 to 3 R^(5a) substituents selected from F, Cl, Br, I, —OH, ═O, C₃₋₆ cycloalkyl, —CN, C₁₋₄ alkyl, —C₁₋₄ alkyl-O—C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ alkoxy; L is a linker selected from the group consisting of C₁₋₄ alkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene, and C₁₋₄ heteroalkylene, wherein L is optionally substituted with from 1 to 3 R^(L) substituents selected from the group consisting of ═O, —OH, —OCH2.phenyl, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ acyl; the subscript m represents the integer 0 or 1; X¹ and X² are each independently selected from the group consisting of absent, —O—, —S(O)—, —S(O)₂— and —N(R^(X))— wherein R^(x) is H, C₁₋₈ alkyl, C₁₋₈ acyl or —S(O)₂(C₁₋₈ alkyl), and wherein if the subscript m is 0 then at least one of X¹ or X² is absent; the subscript n is an integer from 0 to 5; A is selected from the group consisting of hydrogen, C₃₋₁₂ cycloalkyl, C₂₋₁₁ heterocycloalkyl, phenyl having a 3-8 membered carbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S fused thereto or a 5 to 6 membered heteroaryl having a 3-8 membered carbocyclic or heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S fused thereto, and wherein if A is hydrogen then the subscript n is 0; and R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₁₋₈ haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂, ═O, heteroaryl, —(X^(RA))₀₋₁NR^(A1)R^(A2), —(X^(RA))₀₋₁OR^(A1), —(X^(RA))₀₋₁SR^(A1), —(X^(RA))₀₋₁N(R^(A1))C(═O)OR^(A3), —(X^(RA))₀₋₁OC(═O)N(R^(A1))(R^(A2)), —(X^(RA))₀₋₁N(R^(A1))C(═O)N(R^(A1))(R^(A2)), —(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)), —(X^(RA))₀₋₁N(R^(A1))C(═O)R^(A2), —(X^(RA))₀₋₁C(═O)OR^(A1), —(X^(RA))₀₋₁OC(═O)R^(A1), —P(═O)(OR^(A1))(OR^(A2)), —(X^(RA))₀₋₁S(O)₁₋₂R^(A3), —(X^(RA))₀₋₁S(O)₁₋₂N(R^(A1))(R^(A2)), —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)) and —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂(R^(A3)), wherein X^(RA) is selected from the group consisting of C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene; wherein R^(A1) and R^(A2) are independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, tetrahydronapthalene, phenyl, benzyl, heteroaryl, and C₂₋₇ heterocycloalkyl; R^(A3) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, tetrahydronapthalene, phenyl, benzyl, heteroaryl, and C₂₋₇ heterocycloalkyl; wherein if A is a monocyclic C₃₋₁₂ carbocycloalkyl or monocyclic C₂₋₁₁ heterocycloalkyl, then any two R^(A) substituents attached to adjacent atoms on the A ring are optionally combined to form a benzene or a 5 to 6 membered heteroaryl ring; and wherein the aliphatic and aromatic portions of a R^(A) substitutent is optionally substituted with from 1 to 5 R^(RA) substitutents selected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ (halo)alkyl-C(═O)—, C₁₋₄ (halo)alkyl-S(O)₀₋₂—, C₁₋₄ (halo)alkyl-C(═O)N(H)—, C₁₋₄ (halo)alkyl-N(H)—C(═O)—, ((halo)alkyl)₂N—C(═O)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—, C₁₋₄ (halo)alkyl-OC(═O)N(H)—, (halo)alkyl-N(H)—C(═O)O—, ((halo)alkyl)₂N—C(═O)O—, C₁₋₄ alkylamino, C₁₋₄ dialkylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxy, C₂₋₅ heterocycloalkoxy, tetrahydronaphthalene and phenyl wherein phenyl is optionally substituted with 1-3 fluoro, chloro, bromo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkoxy, C₁₋₆ alkylamino, or C₁₋₄ dialkylamino; with the proviso that a compound of Formula I is not 4-(cyclohexylmethoxy)-N-(methylsulfonyl)benzamide; 4-(cyclopentylmethoxy)-N-(methylsulfonyl)benzamide or 4-(cyclobutylmethoxy)-2,5-difluoro-N-(methylsulfonyl)benzamide.
 2. The compound of claim 1 wherein the compound has the formula


3. The compound of claim 1 wherein B is N and R³ is absent.
 4. The compound of claim 1 wherein B is C.
 5. The compound of claim 1 wherein R², R³ and R⁴ are each independently selected from H, F, or Cl.
 6. The compound of claim 1 wherein R² is H, F or Cl; R³ and R⁴ are each H; and R⁵ is an optionally substituted group selected from the group consisting of H, F, Cl, Br, I, —CN, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, and C₁₋₈ alkoxy.
 7. The compound of claim 1 wherein R¹ is C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₁₀ cycloalkyl or —NR^(1A)R^(1B).
 8. The compound of claim 7, wherein R¹ is selected from the group consisting of methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, isopropyl and cyclopropyl.
 9. The compound of claim 1 wherein, R¹ is selected from the group consisting of:


10. The compound of claim 1 wherein R¹ is selected from the group consisting of: methyl, ethyl, tert-butyl, dimethylamino, methylamino, amino, morpholino, azetidino, imidazolyl, 3-hydroxyazetidino, 3-fluoroazetidino, cyclopropyl, pyrrolidinyl, 3,3-difluoroazetidino, tert-butyl, ethyl, 2-methoxyethyl, 3-methoxyazetidino, 2-hydroxyethyl, 3-hydroxypyrrolidinyl, N-methylimidazolyl, tetrahydrorofuranyl, 2-isopropoxyethyl, 3-cyanoazetidino, 2-ethoxyethyl, 2-methoxypropyl, 2-hydroxypropyl, 4-hydroxypiperidinyl and 3-methoxypyrrolidinyl and the following formulas:


11. The compound of claim 1 wherein R¹ is selected from the group consisting of: methyl, ethyl, tert-butyl, dimethylamino, methylamino, amino, morpholino, azetidino, imidazolyl, 3-hydroxyazetidino, 3-fluoroazetidino, cyclopropyl, pyrrolidinyl, 3,3-difluoroazetidino, tert-butyl, ethyl, 2-methoxyethyl, 3-methoxyazetidino, 2-hydroxyethyl, 3-hydroxypyrrolidinyl, and N-methylimidazolyl.
 12. The compound of claim 1 wherein X¹ is —O— or —N(H)—; X² is absent; the subscript m is 1; and -(L)- is an optionally substituted group selected from the group consisting of C₁₋₄ alkylene, C₂₋₄ alkenylene or C₂₋₄ alkynylene.
 13. The compound of claim 1, wherein X¹ is —O— or —N(H)—; X² is absent; the subscript m is 1; and -(L)- is selected from the group consisting of —CH₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—, —C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₃)—CH₂— or —CH₂CH₂CH₂CH₂—.
 14. The compound of claim 13, wherein X¹ is —O—; the subscript m is 1 and -(L)- is —CH₂— or —CH₂—CH₂—.
 15. The compound of claim 1 wherein X¹ is absent; X² is —O— or —N(H)—; the subscript m is 1; and -(L)- is selected from the group consisting of —C(H)₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—, —C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₃)—CH₂— or —CH₂CH₂CH₂CH₂—.
 16. The compound of claim 1 wherein X¹ and X² are absent; the subscript m is 1; and -(L)- is selected from the group consisting of —C(H)₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—, —C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₃)—CH₂— or —CH₂CH₂CH₂CH₂—.
 17. The compound of claim 1 wherein X¹ and X² are absent; the subscript m is 1; and -(L)- is an optionally substituted C₁₋₄ heteroalkylene.
 18. The compound of claim 1 wherein m is 0; X¹ is selected from —O—, and —N(H)—; and X² is absent.
 19. The compound of claim 1 wherein A is an optionally substituted ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, adamantane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[4.1.1]octane, bicyclo[3.3.1]nonane and 1,2,3,4-tetrahydro-1,4-methanonaphthalene, 1,2,3,4-tetrahydroisoquinoline and chroman.
 20. The compound of claim 1 wherein ring A is an optionally substituted ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane, cubane, bicyclo[2.2.2]octane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, piperidinyl, tetrahydrofuranyl, tetrahydronaphthyl, spiro[2,5]octanyl, norpinanyl, spiro[3.5]nonanyl, 8-azabicyclo[3.2.1]octanyl, norbornanyl, spiro[4.5]decanyl, bicyclo[4.1.0]heptane and spiro[5.5]undecanyl.
 21. The compound of claim 1 wherein ring A is an optionally substituted ring selected from the group consisting of azetidine, pyrrolidine, piperidine, homopiperidine, (1R,5S)-8-azabicyclo[3.2.1]octane, 3-oxa-9-azabicyclo[3.3.1]nonane, (1s,4s)-7-azabicyclo[2.2.1]heptane, (1R,4S)-5-azabicyclo[2.1.1]hexane, 7-(trifluoromethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine and quinuclidine.
 22. The compound of claim 1 wherein ring A-(R^(A))_(n) is selected from the group consisting of


23. The compound of claim 1 wherein ring A-(R^(A))_(n) is selected from the group consisting of


24. The compound of claim 1 wherein the group:

is selected from the group consisting of


25. The compound of claim 1 wherein ring A is selected from the group consisting of


26. The compound of claim 1 wherein R^(A) is selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₅ cycloalkyl, C₂₋₄ heterocycloalkyl, F, Cl, Br, I, —OH, —NH₂, —CN, —NO₂, C₁₋₄ alkoxy, —C(═O)—N(R^(A1))(R^(A2)) and —N(R^(A1))(R^(A2)).
 27. The compound of claim 1 wherein R^(A) is methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, ethyl, pentafluoroethyl, cyclopropyl, —F, Cl, —OH, —NH₂ or —CN.
 28. The compound of claim 1 wherein B is C; R³ is H, R² is F, Cl, Br, or I; R⁴ is H; and R⁵ is C₃₋₈ cycloalkyl, wherein said C₃₋₈ cycloalkyl is further optionally substituted with from 1 to 3 R^(5a) substituents selected from F, Cl, Br, I, —OH, ═O, C₃₋₆ cycloalkyl, —CN, C₁₋₄ alkyl, —C₁₋₄ alkyl-O—C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ alkoxy.
 29. The compound of claim 28 wherein R⁵ is C₃₋₈ cycloalkyl.
 30. The compound of claim 1 wherein the group:

is selected from the group consisting of


31. The compound of claim 1 wherein the group:

is selected from the group consisting of


32. A pharmaceutical composition comprising a compound of Formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
 33. A method of treating a disease or condition in a mammal selected from the group consisting of pain, depression, cardiovascular diseases, respiratory diseases, and psychiatric diseases, and combinations thereof, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula I as described in claim 1 or a pharmaceutically acceptable salt thereof.
 34. A method of treating cancer in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula I as described in claim 1 or a pharmaceutically acceptable salt thereof. 